DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review

Abstract

As an important nutrient in the human body, cholesterol can not only provide structural components for the body's cells, but also can be transformed into a variety of active substances to regulate cell signaling pathways. As an important cholesterol synthase, DHCR24 participates in important regulatory processes in the body. The application of DHCR24 in tumor clinical diagnosis and treatment also attracts much attention. This article reviews the structure and regulatory characteristics of DHCR24, and the research of DHCR24 on tumor progression. We summarize the possible mechanisms of DHCR24 promoting tumor progression through reactive oxygen species (ROS), p53, Ras and PI3K-AKT pathways. Through our review, we hope to provide more research ideas and reference value for the application of DHCR24 in tumor prevention and treatment.

Keywords

DHCR24 cholesterol ROS tumor apoptosis

Introduction

A cholesterol metabolism change is one of the most significant metabolic alterations in cancer. The increase of cholesterol promotes the rapid growth of tumor cells and tumor progression.¹ Cholesterol is the structural basis of biological membranes and also serves as a signaling molecule and energy source. In this review, we focus on Δ(24)-sterol reductase (EC:1.3.1.72), an enzyme that is important in cholesterol synthesis. In 2000, Grieve et al found a significant reduction in the expression of a new gene firstly, named selective Alzheimer's disease (AD) indicator 1 (Seladin-1), namely Δ(24)-sterol reductase (DHCR24), in vulnerable regions of the brain in AD patients.² Since then, scientists have been studying it for more than two decades, and its function in tumor progression is being found continuously. In recent years, the research and application of tumor metabolism and microenvironment have been increasing, and lipids, as an important structural substance, have been paid more and more attention and applied in tumor diagnosis and treatment.^3,4 As an important regulatory enzyme of cholesterol synthesis, the role of DHCR24 in tumor prevention and treatment has received more and more attention and research.^5,6

Name Determination

DHCR24 gene encodes a protein called Δ(24)-sterol reductase, which is an oxidoreductase. DIMINUTO/DWARF1 was first identified as a potential gene involved in human steroidogenesis in 1995, which is similar to DIMINUTO/DWARF1 in Arabidopsis.⁷ Later, Greeve et al found that this gene is differentially expressed in the brain regions susceptible to AD, and they named it Selective AD Indicator 1 (Seladin-1).² A year later, Waterham et al found DHCR24 is a kind of an Flavin Adenine Dinucleotide(FAD)-dependent oxidoreductase in humans that reduces the Δ24(25) bond of desmosterol to yield cholesterol. Therefore, the protein is currently called 3β-hydroxysterol Δ24-reductase (also known as Seladin-1) and the gene name is DHCR24.⁸

Structure of DHCR24 Gene and DHCR24

DHCR24 is a protein coding gene located at the p32.3 position of human chromosome 1, with a total length of 46.4kbp, including 9 exons and 8 introns. The length of the open reading frame is about 1.5kbp, encoding a protein containing 516 amino acids with a molecular weight of 60.1kDa.² DHCR24, as a FAD-dependent oxidoreductase, catalyzes the reduction of the Δ24 double bond of sterol intermediates during cholesterol biosynthesis. The protein is mainly located on the membrane structural organelles of cells, such as the endoplasmic reticulum membrane and the Golgi membrane.^2,9,10 DHCR24 is a single transmembrane protein. The 516 amino acids of the protein are divided into three parts by the membrane structure (as shown in Figure 1A). Since 1–22 of the amino acids are a guide sequence that will be excised after guiding it into the cytoplasmic membrane structure. 23–31 of the amino acids are located in the cavity of the membrane structure organelle. The structures of 32 to 52 are helical and embedded in the membrane structure. The rest remains are in the cytosol.⁹ The cytoplasmic fraction is currently known to contain three important protein interaction sites, namely the FAD-binding domain at 111–203, the Mdm2 binding domain at 202–215, and the p53-binding domain at 358–425.^11,12 In addition, the protein also has two caspase cleavage sites, which plays a role in the regulation of apoptosis.^2,9

Figure 1.

Structure and function of DHCR24. A: The structure of DHCR24. DHCR24 is delimited into two structures on either side of the membrane structure by TMD (red). The N-terminal structure is in the organelles, including the signal peptide region (dark gray) and some amino acids (yellow, the specific function is not clear). The C-terminal is a structure located in the cytoplasm, including the FAD binding domain (dark purple), the Mdm2 binding domain (green), the p53 binding domain (light purple), and other amino acid regions (yellow, the specific function is unclear). Some amino acid modifications in all regions have important effects on their function. There is a Caspase cleavage site in the FAD-binding and p53 binding regions respectively. B: Cholesterol synthesis pathway and steps of DHCR24 catalytic reaction. Steps in which DHCR24 is involved in the reaction in the Bloch pathway (light green area). Steps in the Kandutsch-Russell pathway where DHCR24 is involved in a catalytic reaction (light blue area).^34,36 C: Site of DHCR24 catalytic substance reaction in cholesterol synthesis. Substances (6 kinds) produced in the Bloch pathway from lanosterol to cholesterol can also enter the corresponding positions of Kandutsch-Russell pathway after being catalyzed by DHCR24. The C24-C25 double bond of organics is catalyzed to form a single bond of the corresponding organics (shown in the red triangle). Through the intersection of two pathways, cholesterol synthesis is accomplished. SP: Signal peptide, TMD: transmembrane domain, Casp: caspase cleavage site.

Topological analysis of DHCR24 revealed that it has multiple transmembrane domains and multiple phosphorylation and ubiquitination sites in the cytoplasm.¹³ Inhibitors of protein kinase C can reduce the activity of DHCR24, which also confirms the importance of its phosphorylation sites, in which the phosphorylation of T110, Y299 and Y507 residues has been demonstrated to be important for its activity.¹⁴ There is an important NS3-4A protease cleavage site on DHCR24 between residues Cys91 and Thr92, which reduces intracellular deaminosterol conversion to cholesterol after cleavage. Hepatitis C virus (HCV) creates specialized genome replication membranes by cutting DHCR24 and manipulating host lipid metabolism and transport.¹⁵ The FAD-binding domain is an important domain of DHCR24, and changes in its structure often lead to significant changes in function. This conclusion has been confirmed in several cases reported. Through the case study, we found that a homozygous mutation of DHCR24 p.M169T has obvious abnormalities in physical function. From the structural point of view, the mutation of p.M169T has obvious influence on the interaction mechanism of DHCR24 and FAD, and the mutation of p.M169T causes obvious destruction of the whole FAD-binding pocket. Another mutation, p.E191K, triggers a global change in the movement of protein residues, rather than focusing on the cofactor binding pocket, and results in a change in the higher structure of the DHCR24 protein.^16–18 FAD-binding interactions do not only rely on FAD-binding domains, but also promote binding even when proteins are sequentially far apart in higher protein structures. DHCR24 p.Y471S identifies the importance of hydrogen bonds with FAD, and the mutation results in altered FAD interactions.¹⁶ In addition, U18666 A interacts with FAD by forming three new hydrogen bonds with Lys292, Lys367 and Gly438 of DHCR24.¹⁹ This proves that U18666 A blocks DHCR24 activity through allosteric inhibition mechanism at the molecular structure level, which may provide a new idea for the development of novel drugs targeting to block DHCR24 activity. The important amino acid site is summarized in Table 1.

Table 1.

Important Amino Acid Site of DHCR24.

Set point	amino acid	Function	reference
91–92	Cys-Thr	protease cleavage site	15
110	Thr	Phosphorylation	14
122–123	Leu- Glu	caspase cleavage site	2
169	Met	FAD-binding	16
191	Glu	FAD-binding	18
292	Lys	FAD-binding (hydrogen bonds)	19
299	Tyr	Phosphorylation	14
367	Lys	FAD-binding (hydrogen bonds)	19
383–384	Val-Val	caspase cleavage site	9
438	Gly	FAD-binding (hydrogen bonds)	19
471	Tyr	FAD-binding (hydrogen bonds)	16
507	Tyr	Phosphorylation	14

DHCR24 Catalyzes Cholesterol Synthesis

From the process of the name determination and the previous introduction, we can get a general understanding of the function of DHCR24, which is a key oxidoreductase in cholesterol synthesis.¹⁴ Many studies have shown that DHCR24 plays a critical role in the regulation of cellular cholesterol synthesis and homeostasis.^20–24 DHCR24 catalyzes the reduction of the carbon(C)-C double bond to the C-C single bond and produces NADP⁺ in cells by binding to and utilizing NADPH and hydrogen atom derived from the aqueousmilieu in the cell.^8,25–29 To understand the role of DHCR24 in sterol synthesis in detail, we must mention the process of sterol synthesis briefly. Cholesterol synthesis occurs primarily in the liver, and acetyl-CoA or leucine is converted to cholesterol molecules by nearly 30 enzymatic steps, one of which produces lanosterol, followed by another enzymatic reaction to produce cholesterol.³⁰ The enzymatic process from lanosterol to cholesterol can be generated by two pathways, namely Bloch pathway and Kandutsch–Russell pathway.^31–33 DHCR24 plays an important enzymatic role in both pathways, but the difference mainly lies in the order of action of DHCR24. In Bloch pathway, DHCR24 changes the C24-C25 double bond of desmosterol to a single bond in the final reaction step, and then cholesterol is produced. In Kandutsch–Russell pathway, DHCR24 make the C24-C25 double bond of lanosterol to a single bond firstly, and 24,25-dihydrolanosterol is produced, which in turn undergoes an enzymatic reaction to produce cholesterol (as shown in Figure 1B). Even though many researchers have mentioned this process,³⁴ a deep understanding of how cholesterol is synthesized is crucial to studying DHCR24. In fact, the intermediates of both lanosterol to cholesterol pathways can be cross-linked through DHCR24 catalysis. However, the use of both pathways in cholesterol synthesis is highly variable, tissue-specific, flux-dependent, and epigenetically regulated. Sterol deletion in cultured cells increases the throughput of the Bloch pathway, while overexpression of DHCR24 enhances the Kandutsch-Russell pathway.³⁵

Regulation of DHCR24 Gene Expression

Metabolites or Metabolite Analogues Regulate Gene Expression

DHCR24 is a key catalytic enzyme in cholesterol synthesis, so it's expression regulation is bound to be a complex and fine process. In metabolic regulation of enzymes, feedback regulation of enzymes by products or substrates is a common and important regulatory process.^37–39 The concentration of cholesterol available affects DHCR24 gene expression.^40,41 For example, brasssterol can be altered to reduce the accumulation of DHCR24 mRNA and protein levels, thereby reducing cholesterol levels.⁴² In the brain of hyperlipidemia mice, the DHCR24 protein expression level is down-regulated and the ubiquitination level is increased.⁴³ Sterol regulatory element-binding protein 1, Sterol regulatory element-binding protein 2 (SREBP-2) and Liver X receptor (LXR) are important enzymes in sterol synthesis.^44–46 Low concentrations of cholesterol can promote the transcription of regulatory element-binding protein (SREBP). Highly expressed SREBP translocated into the nucleus as a transcription factor to engage and activate transcription of genes involved in cholesterol biosynthesis and lipid homeostasis.⁴⁷ A large number of studies have found that SREBP activity and LXR are associated with DHCR24 expression.^40,48–54 SREBP and LXR make some metabolic intermediates change by regulating the process of cholesterol metabolism, and then affect the expression of DHCR24. Previous studies have found that LXR does not affect the expression of DHCR24 in certain conditions and cell lines, while LXR and SREBP-2 affect the expression of DHCR24 as long as cholesterol synthesis occurred in cells, but the regulatory effect of SREBP-2 is more obvious. This may be because LXR does not have a significant effect on DHCR24-sensitive intermediates, whereas SREBP-2 does. SREBP gene can also regulate DHCR24 expression by regulating promoter binding of adjacent genes. Repressor element 1 (RE1) can inhibit the expression of DHCR24, while RE1-silencing transcription factor (REST) binds to the promoter of RE1 nucleotide sequence and enhances the transcription of DHCR24 after inhibiting RE1 expression. In addition, RE1 and sterol response elements are adjacent, and they are the binding sites of REST and SREBP respectively. This leads us to believe that REST works because it is tightly bound to SREBP, thereby enhancing its ability to up-regulate DHCR24.⁵⁵ Moreover, researchers have mapped this sterol-responsive region (−300/−100, a GC-rich region containing two sterol sensitive response elements and two nearby nuclear factor-γ cofactor site pairs) in the proximal promoter of DHCR24, which can promote the regulation of sterol metabolism.^34,56 SH42, as a DHCR24 inhibitor, does not act directly on the transcription factors of genes, but was mediated through the desmosterol-related loop. The regulatory process of SH42 may be achieved through negative feedback regulation by metabolite analogues.^57,58 Genkwadaphnin (GD), a daphnane-type diterpene orthoester, is a natural product that we recently isolated from a traditional herbal medicine, namely the flower buds of Daphne Genkwa Sieb. It has been found to down-regulate the expression of DHCR24, and this change may also affect the expression of DHCR24 by acting as a metabolite analog.⁵⁹ Apolipoprotein A-IV increases the expression of DHCR24 in cells, possibly by reducing cholesterol levels in cells and thereby increasing DHCR24 expression by inhibiting feedback regulation.⁶⁰ This phenomenon also has been confirmed by a decrease in DHCR24 mRNA levels after overexpression of apolipoprotein M and blocking of lipid transport subsequently.⁶¹ Microarray and RNA-seq dataset analysis have found that the expression of DHCR24 is positively correlated with CYB5A, and the expression of CYB5A can increase the availability of steroid precursors. Therefore, we believe that the regulation of DHCR24 by CYB5A is realized through the feedback regulation of sterol metabolites.⁶² Metabolism in cells is a unified whole, and changes in any one or more metabolic genes will affect the expression of DHCR24 through changes in metabolites.²⁴ The regulation mechanism is summarized in Table 2.

Table 2.

The Regulatory Substances and Modes of DHCR24 Expression.

Factors/substances	Regulatory regions or regulation modes	Reference
Sterol	Region (−300/−100); Feedback regulation by metabolites	34,40,52 –54,56
Brasssterol	Feedback regulation by metabolites	42
SH42	Feedback regulation by metabolic analogs	57,58
GD	Feedback regulation by metabolic analogs	59
Apolipoprotein A-IV	Affects lipid concentration and negatively regulates DHCR24	60
Apolipoprotein M	Affects lipid concentration and negatively regulates DHCR24	61
CYB5A	affects lipid concentration and negatively regulates DHCR24	62
High concentrations low-density lipoprotein cholesterol	cg2716885 methylation regulation	75
HDL-C, glyceryl phosphatide PC (O-36: 5)	cg17901584 methylation regulation	72 –74
-	cg10177197 methylation regulation	69,70
-	cg17475467 methylation regulation	70
-	cg2552667 methylation regulation	70
TGF-β1	Increased H3K27me3 binding to the DHCR24 promoter region and inhibited expression	79
RORγ	Acetylation of histone H3 and H4	64,80,81
SOX9	Up-regulated the expression by combinding with the corresponding sites of DHCR24 gene	6
STAT3	Up-regulated the expression by binding to seven regions in the DHCR24 promoter	78
SRSF3	Splicing of exons 3 and 4 of DHCR24	82
KLF5	Up-regulated the expression by binding to the DHCR24 promoter	40
hsa_circ_0003221	miR-892b/DHCR24 axis	101
hsa_circ_0002099	miR-217-5p/KLF5/DHCR24 axis	102
CircEZH2	miR-217-5p/KLF5/DHCR24 axis	102
hsa_circ_0124696	miR-217-5p/KLF5/DHCR24 axis	102
hsa_circ_0033596	miR-217-5p/KLF5/DHCR24 axis	103
lncRNA ENST00000370438	-	106
miR-7	-	107
miR-124	-	108
Estrogen	Region(−4384/−2892); May act through EBP	84,94
Androgen	Region(-4384/−2892); May act through PI3 K/AKT pathway, Scap or PCAT1	83,87,96
Vitamin C	-	97
Vitamin D	Regulated by PDIA3	98
Thyroid hormones	-	99,100
Insulin	Acting on the promoter through STAT3	78
Fascin actin-bundling protein 1	Interact with DHCR24	109
L. sakei UONUMA strains	Feedback regulation by producing substances	111
miR-24	Inhibiting SR-B1 expression, thereby increasing the expression of DHCR24	113

Structure of DHCR24 Gene Affects its Expression

There is a GC-rich CpG island in the DHCR24 gene, which is conserved in mammals, and these regions are usually regulated by gene methylation.⁶³ In histiocytes with low DHCR24 expression, this region is frequently methylated.^56,64–66 Through pyrosequencing, DHCR24 is found to be methylated in the fetal and placental vascular development,⁶⁷ and differential methylation of this gene is also found in the study of coronary heart disease.⁶³ DHCR24 methylation also changes in some diseases with abnormal blood lipids, and high density lipoprotein cholesterol (HDL-C) affects the occurrence of methylation.⁶⁸ There are multiple methylation sites in DHCR24, including cg17901584, cg10177197 and cg25526676.^69,70 Individuals with methylation at cg25536676 locus have a significantly increased risk of developing diabetes mellitus type 2 (T2DM).⁷⁰ Two sites, cg17901584 and cg10177197, have also been found to be involved in the pathogenesis of T2DM, and a new site, cg17475467, has been found by Meta-analysis.⁷⁰ The cg17901584 site of DHCR24 is a potential target of statins in the treatment of T2DM.^69,71 The cg17901584 site is located within 1 kb upstream of the DHCR24 gene. A lot of research have been done around this methylation site. The Rotterdam study (Epigenome-wide association study on lipids) in 725 participants has been found that the cg17901584 site DNA methylation levels are strongly associated with HDL-C.⁷² The cg17901584 is also identified as a potential obesity-associated locus by a genome-wide obesity-dependent epigenetic methylation study involving 3547 participants,⁷³ which may be due to the altered level of glycerophospholipid PC (O-36: 5).⁷⁴ As an important gene for cholesterol synthesis, the stimulation of external cholesterol concentration in the cells leads to the long-term memory of DHCR24 methylation in the corresponding cells. In a study of the effect of lipid on DNA methylation in circulating cells, the researchers have been found that high level of low-density lipoprotein cholesterol increases the cg2716885 sites methylation of DHCR24.⁷⁵ The memory of this methylation may also affect the offspring, and a study of reduced DHCR24 methylation in the offspring of women with eating disorders during pregnancy seems to provide some evidence.⁷⁶

Gene promoter plays an important role in gene expression. Study of DHCR24 genomic promoter sequences in hepatocellular carcinoma cells (HCC) showed that substitution of −1453 (G to A), −1420 (G to T), −488 (A to C), and −200 (G to C) nucleotide sequences inhibits the activity of DHCR24 gene promoter.⁷⁷ Insulin-activated STAT3 directly binds to seven regions in the DHCR24 promoter and enhances DHCR24 expression.⁷⁸ the KLF5 up-regulated the expression of DHCR24 through promoter.⁴⁰ ChIP experiments showed that TGF-β1 increase the level of H3K27me3, and binding of H3K27me3 to the DHCR24 promoter region led to downregulation of DHCR24 expression. RNA sequencing has confirmed these findings.⁷⁹ Histone acetylation on chromosomes also regulates DHCR24 expression. The decrease in DHCR24 transcription correlates with the recruitment of acetylated histones H3 and H4 to their promoters.⁶⁴ The expression of DHCR24 has a strong correlation with the expression of RORγ,⁸⁰ and it has been found that RORγ regulated the expression of DHCR24 by regulating histone acetylation.⁸¹ In diffuse large B-cell lymphoma, SOX9 targets and transcriptionally activates DHCR24 expression by binding to the SOX9 binding site on the DHCR24 gene directly, and SOX9 also acts as a positive regulator of cholesterol biosynthesis.⁶ In colorectal cancer, SRSF3 directly binds to DHCR24 mRNA, promotes the splicing between exon 3 and exon 4, and ultimately positively regulates the expression of DHCR24.⁸² The regulation mechanism is summarized in Table 2.

Hormones Affect DHCR24 Gene Expression

Sex hormones (estrogen and androgen), as steroid hormones, can increase the expression of DHCR24 by activating their corresponding receptors.^40,83–92 The estrogen responsive region is located in the DHCR24 promoter region (−4384/−2892), and two putative estrogen receptor (ER) elements (−4148/−3789) are found.^84,86 Some substances could regulate the expression of DHCR24 through affecting ER, such as hesperetin could play a role in regulating oxidative stress through this process.⁹³ 17β-estradiol (100 pm∼100 nm) significantly increased DHCR24 expression in mRNA, and the selective ERα agonist propylpyrazole-triol increases DHCR24 expression more than the ERβ agonist diarylpropionitrile. The effect of human estrogen seems to be mainly mediated by ERα, so estrogen has a stronger role in regulating DHCR24 in humans.⁸⁴ This regulation of estrogen may be indirectly regulated by intermediary proteins. Keren Jiang et al found an EBP-like gene in the chickens (Gallus Gallus) genome that encodes a protein highly homologous to human EBP. Its expression can be up-regulated by estrogen and promote the expression of EBP-like downstream genes including DHCR24 in cholesterol synthesis pathway.⁹⁴ The androgen-responsive region is located in the DHCR24 promoter region (−4384/−2892), which contained a putative androgen receptor (AR) element (−3000).^83,85 Due to the presence of an androgen response element in the promoter region of DHCR24, androgen has a significant regulatory effect on the gene expression. It has been found that the expression of DHCR24 is significantly reduced in 23 prostate tumor patients treated with preoperative androgen ablation for 3 months compared with patients treated with surgery alone.⁸⁵ And an research has been suggested that the PI3K/Akt pathway may be involved in the regulation of DHCR24 expression by androgen.⁸⁷ Androgen can also indirectly affect the expression of DHCR24 by up-regulating Scap and promoting the activation of SREBP.⁹⁵ The interaction between AR and PCAT1 can enhance the expression of DHCR24.⁹⁶ As a long noncoding RNAs (lncRNAs), rs7463708 regulates DHCR24 expression via AR in prostate cancer. The risk-associated variant in rs7463708 increases the binding of ONECUT2, a novel AR-interacting transcription factor. The loop-forming distal enhancer can bind to the PCAT1 promoter, and result in up-regulation of PCAT1 after prolonged androgen therapy.⁹⁶ Vitamin C, as an important regulator of cholesterol metabolism, can promote DHCR24 gene expression in fibroblasts.⁹⁷ Vitamin D, a cyclic steroid hormone, could significantly reduce the expression of DHCR24 mRNA in cortical neurons, and this impact is achieved through PDIA3.⁹⁸ Dhcr24 is expressed in the mouse adrenal cortex, and thyroid hormone treatment significantly up-regulated the expression of Dhcr24 in the mouse adrenal cortex.^99,100 The regulation mechanism is summarized in Table 2.

Non-Coding RNA Affects DHCR24 Gene Expression

In bladder cancer (BLCA), overexpression of DHCR24 counteracts the effect of down-regulation of hsa_circ_0003221. MiR-892b is the target gene of hsa_circ_0003221, and miR-892b targets DHCR24. Therefore, hsa_circ_0003221 regulates the progression of BLCA through hsa_circ_0003221/miR-892b/DHCR24 axis.¹⁰¹ Hsa_circ_0002099, circEZH2, circROBO1 (hsa_circ_0124696) and hsa_circ_0033596 (RNA_0033596) inhibit miR-217-5p activity by directly binding to it.^102,103 Furthermore, inhibited miR-217-5p could up-regulate the expression of Kruppel-like factor 5 (KLF5),^104,105 and the KLF5 up-regulated the expression of DHCR24 through promoter.⁴⁰ lncRNA ENST00000370438 can also up-regulate the expression of DHCR24 to promote the proliferation of breast cancer cells.¹⁰⁶ miR-7 blocks the last few steps of the in vitro cholesterol biosynthesis pathway by targeting the DHCR24 transcriptional gene, regulating cholesterol homeostasis at the post-transcriptional level.¹⁰⁷ The presence of miR-124-DHCR24 axis makes miR-124 inhibit the expression of DHCR24 in cells.¹⁰⁸ The regulation mechanism is summarized in Table 2.

Other Regulatory Mechanisms of DHCR24 Expression

DHCR24 can interact with fascin actin-bundling protein 1 and promote laryngeal squamous cell carcinoma progression by regulating signaling pathways related to cholesterol metabolism.¹⁰⁹ rs2294510 is a SNP in the regulatory element of the DIO1 gene promoter region, and its mutation will lead to changes in transcription factor binding sites and differential expression of DHCR24.¹¹⁰ Three L. sakei UONUMA strains inhibited the expression of DHCR24 at the transcriptional level.¹¹¹ This effect may be due to strains producing substances that alter DHCR24 expression. This statement appears to be confirmed by studies in which marine green microalgae extracts contain high levels of carotenoids that enhance the expression of the DHCR24 gene and protein, thereby enhancing the antioxidant and repair activity of A549 (a human lung cancer cell line).¹¹² miR-24 can increase the expression of DHCR24, not because it directly acts on DHCR24, but by inhibiting SR-B1 expression by targeting SR-B1 3′UTR, thereby increasing the expression of DHCR24.¹¹³

The Value of DHCR24 in the Diagnosis and Treatment of Tumors

DHCR24 Is Used as a Biomarker for Tumor Diagnosis

In the prevention and treatment of cancer, early diagnosis is of great significance to improve the survival of patients. As an important sterol metabolism-related gene, DHCR24 expression is affected by a variety of proteins and metabolites. So DHCR24 expression is sensitive to changes in cell homeostasis and can be used as a biomarker for tumor diagnosis.^114,115

Sayeh Ezzikouri et al measured and comprehensively evaluated the accuracy of DHCR24 in patient serum for HCC diagnosis for the first time in a large-scale, multicenter study.¹¹⁶ They found that DHCR24 can be used not only as a diagnostic marker for HCC, but also as a non-invasive detection biomarker for HCV-related liver disease. DHCR24 seems to be more sensitive to infection and progression caused by HCV compared to hepatitis B virus infection. Serum DHCR24 level is the highest in patients with cirrhosis caused by HCV, slightly lower in patients with chronic hepatitis and HCC, but significantly higher than that in normal people, and significantly higher in patients with advanced HCC than that in patients with early HCC. In HCC-C diagnosis, the sensitivity of DHCR24 antibody (70.6%) is higher than AFP (54.8%) and vitamin K antagonist II (42.5%).^116,117 In a tumorigenesis study on human sebaceous gland tumor, the cancer progression associated protein DHCR24 is found to be strongly regulated and detected in human sebaceous gland tumors.¹¹⁸ This discovery suggested that DHCR24 could be used as an auxiliary tool for the diagnosis of human skin diseases. As discussed above, DHCR24 expression is strongly androgen-regulated and is significantly reduced in metastatic castration-recurrent prostate cancer (PRAD) compared with androgen-dependent primary prostate cancer, and these findings suggested that DHCR24 can be used as a potential biomarker for the diagnosis and prognostic analysis of prostate cancer.^89,91,119 Adenocarcinoma in situ, minimally invasive adenocarcinoma and small invasive adenocarcinoma of lung adenocarcinoma were detected by tandem mass tag-labeling liquid chromatography-mass spectrometry, and 4220 differentially expressed proteins are found in their protein expression profiles. Three proteins, including DHCR24, are identified by principal component analysis, western blot and immunohistochemistry (IHC), which could be used to distinguish and diagnose lung adenocarcinoma. Finally, the authors further verified their significance in clinical diagnosis and evaluation of patient treatment by patient survival analysis.¹²⁰ DHCR24 also has diagnostic significance in non-muscle invasive urothelial carcinoma (NMIUC). Real-time quantitative PCR detection of 162 primary tumor tissue specimens of NMIUC patients and IHC analysis of 63 NMIUC patients showed that DHCR24 gene and protein are highly expressed in patients with high-grade NMIUC. Multivariate Cox regression analysis also determined that the expression level of DHCR24 is an independent predictor of disease progression (hazard ratio: 5.464, 95% confidence interval: 1.746-17.099, P = 0.004).¹²¹ Public BLCA gene chip study found that compared with normal bladder tissue, DHCR24 is highly expressed in BLCA cells, and the high expression of DHCR24 in BLCA patients, associates with poor clinical characteristics and survival rate.¹²² Therefore, the progression of BLCA can be determined by detecting the expression of DHCR24 in tissues. The expression of DHCR24 in breast cancer is higher than that in normal breast tissues, especially in Luminal and HER2-positive breast cancer tissues.¹²³ DHCR24 is highly expressed in testicular germ cell tumours (TGCT) of adolescents and adults, ie seminomas and non-seminomatous germ cell tumours, and its expression levels are different in different histological types of TGCT.¹²⁴ Among 364 colorectal cancer (CRC) tissues detected by IHC staining, DHCR24 is found to be highly expressed in 281 (77.2%) CRC tissues, especially in adenocarcinoma tissues (odds ratio = 2.38, P = 0.036). Notably, the expression of DHCR24 is positively correlated with tumor marker CA199 in CRC tissues,⁸² which gave us confidence in the use of DHCR24 a biomarker for cancer diagnosis. The expression of DHCR24 is up-regulated in endometrial carcinoma (EC) and related with poor prognosis positively.⁷⁸ The chi-square frequency of DHCR24 in plasma cellular proteins of ovarian cancer patients shows a large variation.¹²⁵ Patients with rs7551288*A genotype of DHCR24 gene have a 5.31-fold increased risk of melanoma specific death. This genetic variation can be used as a new potential prognostic biomarker for melanoma patients.¹²⁶ The above clinical diagnostic applications are summarized in Table 3.

Table 3.

Application of DHCR24 in Tumor Diagnosis.

Tumor	Sample	Detection/test method	Clinical Significance	Reference
HCC	Serum	enzyme-linked immunosorbent assay	Distinguish between HBV, HCV infection and other liver diseases. Detection sensitivity was higher than AFP	116
HSGT	Pathological tissue	IHC	Used for auxiliary diagnosis	118
PRAD	Pathological tissue	qPCR, IHC, WB	-	119
LUAD	Pathological tissue	LC-MS/MS, APC, WB, IHC	Distinguishing AIS, MIA and SIA	120
NMIUC	Pathological tissue	qPCR, IHC	-	121
BLCA	Public microarray data	Data Analysis	-	122
BRCA	Cells	WB	Distinguishing luminal type and HER2 positive BRCA	123
TGCT	Pathological tissue	IHC	Distinguishing TGCT histological types	124
CRC	Pathological tissue	IHC	Highly expressed in adenocarcinoma and positively correlated with CA199	82
EC	Public data (GSE17025, TCGA); Pathological tissue	Data Analysis, IHC	-	78
OV	Serum	LC–ESI–MS/MS	-	125
SKCM	-	Analysis of genetic variants	Applied to genetic risk analysis	126

Note: AFP: alpha fetoprotein; HSGT: human sebaceous gland tumor; AIS: Adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; SIA: small invasive adenocarcinoma; LUAD: lung adenocarcinoma; LC-MS/MS: liquid chromatography-mass spectrometry; WB: western blot. qPCR: quantitative PCR; BRCA: breast cancer; OV: ovarian cancer; SKCM: melanoma.

Mechanisms of DHCR24 Promotes Tumor Progression

The role of abnormal cholesterol metabolism in tumors has been paid more and more attention.¹²⁷ DHCR24, as an important enzyme related to sterol synthesis, has a positive regulatory effect on the increase of migration and invasion ability of EC, BLCA progression, and breast cancer cell proliferation.^78,101,106 DHCR24 plays an important role in the occurrence and development of tumors.

Lipid rafts are small lipid domains in the cell membrane that are rich in cholesterol and sphingolipids. They play an important role in cell signal transduction and drug efflux.^128–130 Changes in cholesterol-rich membrane lipid rafts have been shown to influence cancer progression. As an important enzyme in the cholesterol biosynthesis pathway, DHCR24 is associated with cellular cholesterol content and lipid raft stabilization.^14,131–133 Depleting cholesterol in the environment inhibits tumor cell growth, migration, and invasion. Inhibition of DHCR24 activity can down-regulate cholesterol biosynthesis and lipid raft formation, and inhibit the growth and metastasis of HCC cells.¹⁴ The presence of lipid raft structures provides strong evidence for the importance of DHCR24.

DHCR24 can affect the occurrence and development of tumor cells by responding to and regulating intracellular reactive oxygen species (ROS).⁸² In prostate cancer, DHCR24 is involved in the regulation of oxidoreductases related to prostate cancer progression, which in turn affects the development of tumors.⁹² DHCR24 is upregulated in cell lines such as human lung cancer in response to oxidative stress and Ras activation.^112,134,135 Intracellular ROS initiate Ras-induced premature senescence,¹³⁶ and Ras-induced senescence is commonly associated with the tumor suppressor p53.¹² Therefore, to study the effect of DHCR24 on tumor progression, it is necessary to discuss the correlation between DHCR24, ROS, Ras, and p53 in tumorigenesis. Silencing of DHCR24 prevented Ras-induced p53 accumulation, suggesting that DHCR24 is an important mediator of Ras-induced p53 responses and that this process may be mediated by the PI3K-AKT pathway.^12,137,138 Since DHCR24 has Mdm2 and p53 binding sites,^11,12 intracellular DHCR24 will interact with p53 and Mdm2, preventing the ubiquitination and degradation of p53 by Mdm2, leading to p53 accumulation and subsequent cell cycle arrest.^12,139,140 In addition, the binding of DHCR24 to p53 in the nucleus results in the decreased acetylation level of lysine 373 and lysine 382 of p53, and the non-acetylated p53 will reduce the activity and stability of p53 sequence-specific DNA binding.^85,141,142 Through the above pathways, DHCR24 can inhibit DNA damage repair of p53. The endoplasmic reticulum localization of DHCR24 confirms the hypothesis that it is directly involved in the oxidative stress response, and the fact that its intracellular localization changes under oxidative and carcinogenic conditions confirm the altered function of DHCR24 in different cellular locations.³⁴ Previously we have mentioned that DHCR24 promotes cholesterol synthesis and stabilizes multiple signaling pathway-related proteins on lipid rafts. Interestingly, Ras is immobilized on lipid rafts and activated by multiple factors, such as ROS,^143,144 and activated Ras further affects Mdm2 phosphorylation through the PI3K-AKT pathway.^145,146 Phosphorylated Mdm2 translocates to the nucleus and binds with p53, and then, this complex transports p53 into the cytoplasm. However, the DHCR24 binded to Mdm2-p53 in the cytoplasm, leads to the failure of p53 to be properly degraded by the proteasome,¹⁴⁷ and results in p53 accumulation and inhibition of cell cycle and apoptosis.

Overexpression of Dhcr24 gene in mouse cardiomyocytes can significantly reduce the occurrence of mitochondrial swelling. Bax translocation and cytochrome c release are significantly inhibited, and activation of caspase-9 and caspase-3 is also reduced in the overexpressed cells. Similar results described above are also obtained in rat embryonic cardiomyocytes H9c2, where the apoptotic index is decreased after Dhcr24 gene overexpression.¹⁴⁸ DHCR24 is also found to exhibit anti-apoptotic properties by inhibiting caspase-3 activation in germ cell tumors and pituitary adenomas.^2,124,149 Furthermore, we found that DHCR24 overexpression increases the levels of p-PI3K, HKII and p-AKT, and treatment of DHCR24 overexpression cells with PI3K inhibitor (LY294002) or HKII inhibitor (3-BrPA) reduces HKII expression and increases Bax translocation and cytochrome c release. The apoptosis index is significantly increased.¹⁴⁸ PI3K-AKT signaling pathway affects cell apoptosis,^150,151 and DHCR24 can activate PI3K-AKT signaling pathway to regulate tumor cell apoptosis.^143,152 The above processes are accomplished through Ras highly likely.^153,154 It was also found that DHCR24 expression affects AKT activity in EC and other studies.^132,155,156 The study that a p53-PI3P signalsome regulates nuclear AKT activation allows us to believe that DHCR24 may also affect PI3K-AKT via p53.¹⁵⁷ Studies on the role of DHCR24 in apoptosis are abundant. Overexpression DHCR24 increases the expression of Bcl-xl, Mcl-1 and Bcl-2 and decreases the expression of Bad and Bax in Karpas-422 cells.⁶ DHCR24 effectively protects neurons from β-amyloid-mediated toxicity and prevents apoptosis by inhibiting caspase-3 activation in pituitary adenomas, which may be achieved through sstr, especially sstr3.¹⁴⁹

Due to the double-edged sword role of ROS in tumor cell progression,¹⁴³ and cell apoptosis would be promoted by ROS acted on cells.^158–161 DHCR24 is up-regulated in response to oxidative stress, and DHCR24 affects p53 accumulation, while ROS also affects apoptosis through p53.¹⁶² Now that, we know that DHCR24 regulates oxidative stress, how does DHCR24 regulate oxidative stress-induced apoptosis? It was found that the ROS scavenging function of DHCR24 persists as long as its FAD-binding domain is intact, regardless of whether its transmembrane domain is present intact or not.⁹ When DHCR24 is highly expressed in cells, it can prevent oxidative stress-induced apoptosis and can play an antioxidant role by scavenging ROS.^34,163,164 After DHCR24 silenced in CRC, ROS level is significantly increased and cell apoptosis is significantly aggravated.⁸² The high expression of DHCR24 can reduce the oxidative stress induced by hydrogen peroxide and the ability of cell apoptosis in melanoma.¹⁶⁵ We mentioned that ROS can activate Ras and then inhibit apoptosis early, which seems to contradict the fact that ROS promotes cell apoptosis as we have just elaborated.^143,144 The role of DHCR24 in regulating tumor cell progression through oxidative stress is complex. Besides ROS, there are a large number of other factors that can activate Ras, and DHCR24 may only have a scavenging effect on a little part of ROS. In contrast to this inhibitory effect, its role in stabilizing Ras activation by lipid rafts is more pronounced. Overall, the role of DHCR24 in inhibiting tumor progression is far less than that in promoting tumor progression. To sum up, as shown in Figure 2, ROS and other factors causes cell damage and induces high DHCR24 expression. The DNA damage repair measures of p53 are ineffective due to the high expression of DHCR24. Ras is activated by some factors to stabilize the lipid raft structure and promotes cell proliferation through PI3K-AKT and Ras-Raf signaling pathways.¹⁴⁴ When damage is accumulated and apoptosis is suppressed, the cells mutate and survive forever. In the study of rat embryonic fibroblasts and human WI38 fibroblasts, DHCR24 is found to be involved in the regulation of Ras-induced cell transformation and senescence of human and rodent cells, and the transformed rat embryonic fibroblasts cells become tumorigenic and form tumors in nude mice.¹²

Figure 2.

Mechanisms of DHCR24 in promoting tumor growth and inhibiting apoptosis. ROS can enhance intracellular DHCR24 expression. High levels of DHCR24 increase cholesterol synthesis. Increased cholesterol stabilization Ras on the lipid rafts.¹¹² Ras enhances PI3K-AKT and Ras-Raf pathway, thereby promoting cell growth and inhibiting cell apoptosis.^6,144,148 DHCR24 in the nucleus can inhibit the acetylation of p53 and reduce the stability of p53 binding DNA.^85,141 The activation of Akt leads to phosphorylated Mdm2 into nucleus, and binding with p53. Mdm2 and p53 are transported out of the nucleus as complex.¹⁴⁵ All these effects inhibit p53 DNA damage repair. The extracellular complexes formed by Mdm2, p53 and DHCR24 inhibit the degradation or entry into the nucleus of p53, resulting in accumulation extracellular.¹⁴⁷ This result led to inhibit in cell cycle and apoptosis. Intracellular DHCR24 can clear ROS from cells and exert antioxidant function (purple background area). As long as the FAD domain (deep purple) of DHCR24 is intact, the presence or absence of other domains does not affect its ROS clearance function.⁹ (DHCR24 structure description, Red: TMD; Dark gray: signal peptide area; Dark purple: FAD binding domain; Green: Mdm2 binding domain; Light purple: p53 binding domain; Other amino acid region: yellow).

DHCR24 contributed to tumor progression through multiple pathways. To some extent, Hedgehog signaling enhanced by DHCR24 promotes the growth of breast cancer stem cell-like cells, maintained ALDH⁺ cell population and significantly increased Gli3 and PTCH1 mRNA levels.¹²³ The abnormal expression of DHCR24 may affect the progression of prostate cancer.⁹⁶ Primary prostate tumors with lower DHCR24 mRNA level have higher metastasis after radical prostatectomy.¹⁶⁶ Insulin can activate STAT3, which directly binds to seven regions in the DHCR24 promoter, leads to enhanced migration and invasion of endometrial cancer.⁷⁸

DHCR24 Is a Potential Target for Tumor Therapy

With the deepening of biomedical research, the understanding of the biological functions of cholesterol biosynthesis intermediates has changed significantly. In particular, DHCR24 has attracted much attention as a potential drug target.^36,167

For the first time, an anti-cancer peptide (ACP, herein named Q7) has been shown to have anti-cancer effect on EC cells by down-regulating DHCR24 expression, thereby inhibiting their tumorigenicity such as metastasis and proliferation. Lipo-PEI-PEG-complex enhances the anti-cancer activity of this substance in vitro. The combination of Lipo-PEI-PEG-complex-Q7 with doxorubicin or paclitaxel shows a stronger synergistic effect.¹³² DHCR24 is specifically expressed on the surface of HCC cell lines. Monoclonal antibody (2-152a MAb) against DHCR24 recognizes the cell surface antigen recognition domain and shows unique anti-HCV activity. DHCR24 on the surface of HCC cells is internalized after activation and induction, and then regulates cholesterol synthesis and affects tumor progression. This property of DHCR24 makes it a valuable target for the treatment of HCV-related HCC, and 2–152a MAb appears to be useful for such targeted therapy.¹⁶³

SH42 acts as an inhibitor of DHCR24, which does not directly act on the transcription factors of genes, but is mediated through the desmosterol-associated loop. The above process may be achieved through the negative feedback regulation of metabolite analogues.^57,58 In view of the important role of DHCR24, the possibility of using SH42 as a DHCR24 inhibitor drug can be further tested. GD can inhibit the growth, migration and invasion of hepatocellular carcinoma cells. GD decreased intracellular DHCR24 mRNA and protein levels and cholesterol levels. These results indicate that GD exhibits anti-tumor activity in vivo, which is related to the inhibition of DHCR24-induced cholesterol biosynthesis, and can be used as a potential drug for the treatment of HCC.⁵⁹

Because statins may be associated with CpG methylation (cg17901584, cg10177197, cg17475467) of DHCR24 gene.^69,168 The expression of DHCR24 changes in patients treated with statins and the progression of the tumor is affected.¹⁶⁹ Co-treatment with U18666 A, a chemical inhibitor of DHCR24, increases the proportion of apoptotic cells. Exposure to U18666 A increases the levels of BIM and p27^kip1, especially in resistant cells. U18666 A decreases the uptake of glutamate by cells, and this inhibition is achieved due to its inhibition of DHCR24.¹⁷⁰ In addition, combination treatment results in a significant activation of caspase3/7 in LM16R cells compared with single drug exposure. Therefore, inhibitors of DHCR24 can be developed as effective anti-tumor drugs, and irbesartan, which can inhibit DHCR24 activity, seems to be able to be a suitable drug.¹⁷¹

Patients with castration-resistant prostate cancer treated with androgen deprivation plus docetaxel have a high survival rate. However, a significant proportion of these patients eventually develop resistance to docetaxel within a few months. The combination of docetaxel and Caffeic acid phenethyl ester can reduce the expression of cholesterol biosynthesis gene DHCR24 in tumor and inhibit the proliferation and survival of docetaxel-resistant cancer cells.²⁴ Therefore, DHCR24 was a potential target for enhancing drug sensitivity in cancer therapy. DHCR24 silencing in TGCT cell lines can enhance the response to cisplatin treatment, reduce cell viability, and increase the expression of apoptotic markers.¹²⁴ Sitagliptin can effectively inhibit DHCR24-mediated cholesterol biosynthesis in gestational trophoblastic neoplastic cells. Down-regulated DHCR24 expression could enhance methotrexate (MTX) induced cytotoxicity. Targeting Dipeptidyl Peptidase 4/DHCR24 signaling may help to increase the sensitivity of MTX-resistant gestational trophoblastic neoplastic to MTX treatment.¹⁷² The expression of DHCR24 in EC is negatively correlated with the expression of progesterone receptor. Therefore, DHCR24 affects the response of EC cells to progesterone, and silencing DHCR24 enhances the sensitivity of EC cells to medrosylprogesterone acetate treatment.⁷⁸ The role of DHCR24 in tumor treatment is summarized in Table 4.

Table 4.

Role of DHCR24 in Cancer Drug Therapy.

Substance/Drugs	Tumor	Mechanism of action	Reference
ACP (Q7)	EC	Reduce DHCR24 expression, and inhibit EC metastasis and proliferation	132
2-152a MAb	HCC	Antigen-antibody binding affects DHCR24 function of cell surface antigen recognition domain, and in turn affects DHCR24 internalization and cholesterol synthesis	163
SH42	-	Reduce DHCR24 expression by the negative feedback regulation of metabolite analogues	57,58
Statins	-	Regulate DHCR24 expression by changing the methylation status of DHCR24	69,168,169
Docetaxel and Caffeic acid phenethyl ester	PRAD	Reduce the expression of DHCR24, and inhibit the proliferation and survival of docetaxel-resistant cancer cells	24
GD	HCC	Reduce DHCR24 expression, and inhibit the growth, migration and invasion of HCC	59
Cisplatin	TGCT	Silencing DHCR24 enhances cisplatin susceptibility, reduces cell viability, increases the apoptosis	124
Sitagliptin	GTN	Reduce DHCR24 expression, and enhance MTX sensitivity by Dipeptidyl Peptidase 4/DHCR24 signaling regulated	172
Irbesartan	SKCM	Inhibit DHCR24 activity, and increase the apoptosis of drug resistant cells	171
MPA	EC	DHCR24 affects the response of EC cells to progesterone, and Silencing DHCR24 enhances drug susceptibility	78

Note: GTN: gestational trophoblastic neoplastic; MPA: medrosylprogesterone acetate.

Cancer Therapy Targeting DHCR24 is Becoming a Reality

In recent decades, the incidence and mortality of malignant tumors have been on the rise, and have become the second leading cause of death in the world. Worldwide, an estimated 19.3 million new cancer casesand almost 10.0 million cancer deathsoccurred in 2020. And the global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020.¹⁷³ In 2020, the number of cancer-related deaths in China reached over 2.0 million, an increase of 21.6% compared with 2005.¹⁷⁴ In the early stages of cancer development, surgery is one of the main ways to completely cure the tumor, and this conclusion has been accepted by clinical practice. However, unfortunately, most tumors are in the middle and advanced stage by the time they are clearly diagnosed, and surgery is difficult to completely remove. Radiation therapy and chemotherapy are also the main means of traditional cancer treatment, but this kind of treatment has more serious toxic side effects, which will reduce the quality of life of patients. In recent years, with the continuous progress of tumor research, immunotherapy has been increasingly applied to tumor therapy, and cholesterol, as an important component of cell membranes and organelle membranes, has an important effect on various lymphocytes and bone marrow cells in the tumor microenvironment.^3,4 DHCR24, as an important enzyme in cholesterol synthesis, has also been found to play an important role in the regulation of immunity. Studies have found that DHCR24 has significant anti-inflammatory effects.¹⁷⁵ Overexpression of DHCR24 can significantly reverse the polarization of BV-2 cells treated with amyloid-β25–35, inhibit the inflammatory response of BV-2 cells, and inhibit the transformation of their cell phenotype from “M2” type to “M1”type (“M1” and “M2” are the types of BV-2 cells given in the literature. “M1” type cells can increase inflammation by secreting a large number of pro-inflammatory cytokines, known as pro-inflammatory. “M2” type cells inhibit the secretion of inflammatory cytokines, and these cells are characterized by inflammation inhibition and are called anti-inflammatory.).¹⁷⁶ The seven immune gene (including DHCR24) prognostic risk models constructed, can reflect the content of CD8⁺ T cells, neutrophil infiltration and macrophage infiltration in the immune microenvironment of acute myeloid leukemia patients.¹⁷⁷ The immune changes induced by DHCR24 regulation of deaminosterol accumulation may be a feasible mechanism. Desmosterol is an intermediate of cholesterol biosynthesis and a key molecule that integrates cholesterol homeostasis and immune response in macrophages. Overexpression of DHCR24 leads to desmosterol depletion, which increases the interferon response and weakens the expression of anti-inflammatory macrophage markers.⁴¹

As an important substance in tissues, cholesterol plays an important role in tumor metabolism. With the in-depth research on tumor microenvironment and tumor metabolism, the regulation of tumor metabolism and metabolite changes has a broader application value in tumor diagnosis and treatment. At present, the drug development of DHCR24 mainly focuses on the control of cholesterol and metabolites, and these drugs have gradually been found to play an important role in the prevention and treatment of tumors. The study found that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, resulting in a large accumulation of cellular deaminosterol in patients’ cells and serum.^178,179 The increase of deaminosterol level in tissues can affect the expression of ABC transporter and the structure of lipid rafts in cells,³⁹ thus affecting the drug resistance of tumors. In an animal study, Agomelatine was found to inhibit Akt-mTOR and Hes1-Notch1 signaling pathways by upregulating DHCR24 activity.¹⁸⁰ Although no clinical studies have evaluated the clinical effect of agomelatine in the treatment of tumors, the treatment of colorectal cancer and breast cancer has been experimentally confirmed.^181,182 Trimetazidine increases the expression of DHCR24 gene and reduces the oxidative stress of cells.¹⁸³ It is beneficial to treat triple-negative breast cancer with high content of acetyl-CoA acyltransferase 1.¹⁸⁴ Irbesartan reduces cholesterol activity in HepG2 cells by competitively inhibiting DHCR24 enzyme activity,¹⁷¹ and can enhance the sensitivity of pancreatic tumor cells to drugs.¹⁸⁵ We mentioned earlier that statins regulate the expression of DHCR24. Clinical studies have found that statin therapy can extend the survival of some patients treated with a combination of first-line chemotherapy drugs, such as colorectal cancer, multiple myeloma and metastatic pancreatic cancer.^186–188 In a Phase II clinical trial, simvastatin combined with the EGFR inhibitor gefitinib was found to have a better anti-tumor effect than EGFR inhibitor alone in the treatment of non-small cell lung cancer.^189,190 In addition, clinical data also indicate that the antitumor effects of statins are dose and time dependent.¹⁹¹

Summary and Prospect

Cholesterol synthesis is an important metabolic pathway, and the change of metabolism will affect the normal growth of cells and lead to the occurrence of tumors.^192–194 We review some information about DHCR24, an important enzyme in cholesterol synthesis, and detail the role in tumor diagnosis, development and treatment. The expression of DHCR24 is exquisitely regulated in many ways; therefore, cholesterol synthesis is tightly regulated in normal cells. Once the regulation is out of control, the progress of cells will be greatly affected, cancerous, and promoted the progress of tumors.^195,196 Therefore, understanding DHCR24, an important regulatory enzyme of cholesterol synthesis, will be of great significance for the diagnosis and treatment of tumors, and play an important role in the prevention and treatment of tumors in the future.

Conclusion

We reviewed the role of DHCR24 in regulating cholesterol synthesis from the aspects of its structure and expression, and summarized its role in tumor diagnosis and treatment. DHCR24 regulates cholesterol metabolism, affects the structure of lipid rafts on cell membranes, regulates intracellular ROS levels, and interacts with p53 and other proteins. All of these effects affect the progression of the tumor. Therefore, DHCR24 also provides a certain target for tumor therapy. With the further study of DHCR24, its role in tumor diagnosis and treatment will be more important.

Footnotes

Acknowledgements

Not applicable.

Authors’ Contributions:

Literature collation and writing, X.F.; Article design and reviser, Z.W.; Funding acquisition, Z.W.; All authors have read and agreed to the published version of the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research was funded by Seed Foundation of Tianjin Medical University Cancer Institute and Hospital (#1703).

Seed Foundation of Tianjin Medical University Cancer Institute and Hospital, (grant number #1703).

ORCID iD

Zhaosong Wang

References

Mullen

Longo

, et al. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 2016;16(11):718-731. doi:https://doi.org/10.1038/nrc.2016.76

Greeve

Hermans-Borgmeyer

Brellinger

, et al. The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress. J Neurosci. 2000;20(19):7345-7352. doi:https://doi.org/10.1523/JNEUROSCI.20-19-07345.2000

Yan

Zheng

Jiang

, et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell. 2023;41(7):1276-1293.e11. doi:https://doi.org/10.1016/j.ccell.2023.04.016

Wang

Yan

Kong

, et al. Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma. Nat Commun. 2023;14(1):4367. doi:https://doi.org/10.1038/s41467-023-39683-z

Jiang

Xia

. Hsa_circ_0003221 facilitates the malignant development of bladder cancer cells via resulting in the upregulation of DHCR24 by targeting miR-892b. Investig Clin Urol. 2022;63(5):577-588. doi:https://doi.org/10.4111/icu.20220153

Shen

Zhou

Nie

, et al. Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 + diffuse large B-cell lymphomas. Blood. 2022;139(1):73-86. doi:https://doi.org/10.1182/blood.2021012327

Takahashi

Gasch

Nishizawa

, et al. The DIMINUTO gene of Arabidopsis is involved in regulating cell elongation. Genes Dev. 1995;9(1):97-107. doi:https://doi.org/10.1101/gad.9.1.97

Waterham

Koster

Romeijn

, et al. Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet. 2001;69(4):685-694. doi:https://doi.org/10.1086/323473

Liu

, et al. The membrane topological analysis of 3β-hydroxysteroid-Delta24 reductase (DHCR24) on endoplasmic reticulum. J Mol Endocrinol. 2012;48(1):1-9. doi:https://doi.org/10.1530/JME-11-0132

10.

Sharpe

Brown

. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem. 2013;288(26):18707-18715. doi:https://doi.org/10.1074/jbc.R113.479808

11.

Punta

Coggill

Eberhardt

, et al. The Pfam protein families database. Nucleic Acids Res. 2012;40(Database issue):D290-D301. doi:https://doi.org/10.1093/nar/gkr1065

12.

Miloslavskaya

Demontis

, et al. Regulation of cellular response to oncogenic and oxidative stress by seladin-1. Nature. 2004;432(7017):640-645. doi:https://doi.org/10.1038/nature03173

13.

Zerenturk

Sharpe

Brown

. DHCR24 associates strongly with the endoplasmic reticulum beyond predicted membrane domains: implications for the activities of this multi-functional enzyme. Biosci Rep. 2014;34(2):e00098. doi:https://doi.org/10.1042/BSR20130127

14.

Luu

Zerenturk

Kristiana

, et al. Signaling regulates activity of DHCR24, the final enzyme in cholesterol synthesis. J Lipid Res. 2014;55(3):410-420. doi:https://doi.org/10.1194/jlr.M043257

15.

Tallorin

Villareal

Hsia

, et al. Hepatitis C virus NS3-4A protease regulates the lipid environment for RNA replication by cleaving host enzyme 24-dehydrocholesterol reductase. J Biol Chem. 2020;295(35):12426-12436. doi:https://doi.org/10.1074/jbc.RA120.013455

16.

Cocciadiferro

Mazza

Vecchio

, et al. Exploiting in silico structural analysis to introduce emerging genotype-phenotype correlations in DHCR24-related sterol biosynthesis disorder: A case study. Front Genet. 2023;14:1307934. doi:https://doi.org/10.3389/fgene.2023.1307934

17.

Rohanizadegan

Sacharow

. Desmosterolosis presenting with multiple congenital anomalies. Eur J Med Genet. 2018;61(3):152-156. doi:https://doi.org/10.1016/j.ejmg.2017.11.009

18.

Dias

Rupps

Millar

, et al. Desmosterolosis: an illustration of diagnostic ambiguity of cholesterol synthesis disorders. Orphanet J Rare Dis. 2014;9(1):94. doi:https://doi.org/10.1186/1750-1172-9-94

19.

Quan

Chen

Sun

, et al. The mechanism of the effect of U18666a on blocking the activity of 3β-hydroxysterol Δ-24-reductase (DHCR24): Molecular dynamics simulation study and free energy analysis. J Mol Model. 2016;22(2):46. doi:https://doi.org/10.1007/s00894-016-2907-2

20.

Shen

Zhou

. Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 + diffuse large B-cell lymphomas. Am J Hematol. 2022;139(1):73-86. doi:https://doi.org/10.1182/blood.2021012327

21.

Chen

, et al. The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis. Int J Biol Sci. 2023;19(9):2879-2896. doi:https://doi.org/10.7150/ijbs.84994

22.

Crameri

Biondi

Kuehnle

, et al. The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and abeta generation in vivo. EMBO J. 2006;25(2):432-443. doi:https://doi.org/10.1038/sj.emboj.7600938

23.

Zhang

Huang

Guo

, et al. DHCR24 Reverses Alzheimer's disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice. Acta Neuropathol Commun. 2023;11(1):102. doi:https://doi.org/10.1186/s40478-023-01593-y

24.

Wang

Tseng

, et al. Combination treatment of docetaxel with caffeic acid phenethyl ester suppresses the survival and the proliferation of docetaxel-resistant prostate cancer cells via induction of apoptosis and metabolism interference. J Biomed Sci. 2022;29(1):16. doi:https://doi.org/10.1186/s12929-022-00797-z

25.

Schaaf

Koster

Katsonis

, et al. Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. Am J Med Genet A. 2011;155a(7):1597-1604. doi:https://doi.org/10.1002/ajmg.a.34040

26.

Luu

Hart-Smith

Sharpe

, et al. The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally. J Lipid Res. 2015;56(4):888-897. doi:https://doi.org/10.1194/jlr.M056986

27.

Zerenturk

Kristiana

Gill

, et al. The endogenous regulator 24(S),25-epoxycholesterol inhibits cholesterol synthesis at DHCR24 (Seladin-1). Biochim Biophys Acta. 2012;1821(9):1269-1277. doi:https://doi.org/10.1016/j.bbalip.2011.11.009

28.

Jansen

Wang

Greco

, et al.

What dictates the accumulation of desmosterol in the developing brain?

FASEB J. 2013;27(3):865-870. doi:https://doi.org/10.1096/fj.12-211235

29.

Mercer

. Inhibitors of sterol biosynthesis and their applications. Prog Lipid Res. 1993;32(4):357-416. doi:https://doi.org/10.1016/0163-7827(93)90016-p

30.

Einarsson

Nilsell

Leijd

, et al. Influence of age on secretion of cholesterol and synthesis of bile acids by the liver. N Engl J Med. 1985;313(5):277-282. doi:https://doi.org/10.1056/NEJM198508013130501

31.

Bloch

. The biological synthesis of cholesterol. Science. 1965;150(3692):19-28. doi:https://doi.org/10.1126/science.150.3692.19

32.

Kandutsch

Russell

. Preputial gland tumor sterols. 2. The identification of 4 alpha-methyl-Delta 8-cholesten-3 beta-ol. J Biol Chem. 1960;235(8):2253-2255. PMID: 14404283.

33.

Kandutsch

Russell

. Preputial gland tumor sterols. 3. A metabolic pathway from lanosterol to cholesterol. J Biol Chem. 1960;235(8):2256-2261. PMID: 14404284.

34.

Zerenturk

Sharpe

Ikonen

, et al. Desmosterol and DHCR24: Unexpected new directions for a terminal step in cholesterol synthesis. Prog Lipid Res. 2013;52(4):666-680. doi:https://doi.org/10.1016/j.plipres.2013.09.002

35.

Mitsche

McDonald

Hobbs

, et al. Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. Elife. 2015;4:e07999. doi:https://doi.org/10.7554/eLife.07999

36.

Müller

Hank

Giera

, et al. Dehydrocholesterol reductase 24 (DHCR24): Medicinal chemistry, pharmacology and novel therapeutic options. Curr Med Chem. 2022;29(23):4005-4025. doi:https://doi.org/10.2174/0929867328666211115121832

37.

Acosta-Calle

Miller

AJM

. Tunable and switchable catalysis enabled by cation-controlled gating with crown ether ligands. Acc. Chem. Res. 2023;56(8):971-981. doi:https://doi.org/10.1021/acs.accounts.3c00056

38.

Luo

Yang

. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21(4):225-245. doi:https://doi.org/10.1038/s41580-019-0190-7

39.

Javitt

. Alzheimer's disease: Neuroprogesterone, epoxycholesterol, and ABC transporters as determinants of neurodesmosterol tissue levels and its role in amyloid protein processing. J Alzheimers Dis. 2013;35(3):441-450. doi:https://doi.org/10.3233/JAD-130044

40.

Daimiel

Fernández-Suárez

Rodríguez-Acebes

, et al. Promoter analysis of the DHCR24 (3β-hydroxysterol Δ(24)-reductase) gene: Characterization of SREBP (sterol-regulatory-element-binding protein)-mediated activation. Biosci Rep. 2012;33(1):57-69. doi:https://doi.org/10.1042/BSR20120095

41.

Zhang

McDonald

Aryal

, et al. Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis. Proc Natl Acad Sci U S A. 2021;118(47):e2107682118. doi:https://doi.org/10.1073/pnas.2107682118

42.

Kuwabara

Ohta-Shimizu

Fuwa

, et al. Ergosterol increases 7-dehydrocholesterol, a cholesterol precursor, and decreases cholesterol in human HepG2 cells. Lipids. 2022;57(6):303-311. doi:https://doi.org/10.1002/lipd.12357

43.

Wang

Zhang

, et al. High fat diet induces brain injury and neuronal apoptosis via down-regulating 3-β hydroxycholesterol 24 reductase (DHCR24). Cell Tissue Res. 2023;393(3):471-487. doi:https://doi.org/10.1007/s00441-023-03804-3

44.

Shao

Espenshade

. Expanding roles for SREBP in metabolism. Cell Metab. 2012;16(4):414-419. doi:https://doi.org/10.1016/j.cmet.2012.09.002

45.

Goldstein

DeBose-Boyd

Brown

. Protein sensors for membrane sterols. Cell. 2006;124(1):35-46. doi:https://doi.org/10.1016/j.cell.2005.12.022

46.

Wang

Tontonoz

. Liver X receptors in lipid signalling and membrane homeostasis. Nat Rev Endocrinol. 2018;14(8):452-463. doi:https://doi.org/10.1038/s41574-018-0037-x

47.

Wang

Xia

, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature. 2020;580(7804):530-535. doi:https://doi.org/10.1038/s41586-020-2183-2

48.

Bae

Paik

. Cholesterol biosynthesis from lanosterol: Development of a novel assay method and characterization of rat liver microsomal lanosterol delta 24-reductase. Biochem J. 1997;326(Pt 2):609-616. doi:https://doi.org/10.1042/bj3260609

49.

Horton

Shah

Warrington

, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci U S A. 2003;100(21):12027-12032. doi:https://doi.org/10.1073/pnas.1534923100

50.

Demoulin

Ericsson

Kallin

, et al. Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3-kinase and sterol regulatory element-binding proteins. J Biol Chem. 2004;279(34):35392-35402. doi:https://doi.org/10.1074/jbc.M405924200

51.

Kallin

Johannessen

Cani

, et al. SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55 gamma. J Lipid Res. 2007;48(7):1628-1636. doi:https://doi.org/10.1194/jlr.M700136-JLR200

52.

Martens

Zhan

Voortman

, et al.

Activation of Liver X Receptors and Peroxisome Proliferator-Activated Receptors by Lipid Extracts of Brown Seaweeds: A Potential Application in Alzheimer's Disease?

Nutrients. 2023;15(13):3004. doi:https://doi.org/10.3390/nu15133004

53.

Zhou

. Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation. EMBO Mol Med. 2023;15(8):e16845. doi:https://doi.org/10.15252/emmm.202216845

54.

Wang

Rogers

Stayrook

, et al. The selective Alzheimer's disease indicator-1 gene (Seladin-1/DHCR24) is a liver X receptor target gene. Mol Pharmacol. 2008;74(6):1716-1721. doi:https://doi.org/10.1124/mol.108.048538

55.

Tint

Pan

Shang

, et al. Desmosterol in brain is elevated because DHCR24 needs REST for robust expression but REST is poorly expressed. Dev Neurosci. 2014;36(2):132-142. doi:https://doi.org/10.1159/000362363

56.

Zerenturk

Sharpe

Brown

. Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: Cooperative induction of key enzymes in lipid synthesis by sterol regulatory element binding proteins. Biochim Biophys Acta. 2012;1821(10):1350-1360. doi:https://doi.org/10.1016/j.bbalip.2012.07.006

57.

Körner

Zhou

Müller

, et al. Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. Proc Natl Acad Sci U S A. 2019;116(41):20623-20634. doi:https://doi.org/10.1073/pnas.1911992116

58.

Müller

Hemmers

Bartl

, et al. New chemotype of selective and potent inhibitors of human delta 24-dehydrocholesterol reductase. Eur J Med Chem. 2017;140:305-320. doi:https://doi.org/10.1016/j.ejmech.2017.08.011

59.

Guo

Qiu

, et al. Genkwadaphnin inhibits growth and invasion in hepatocellular carcinoma by blocking DHCR24-mediated cholesterol biosynthesis and lipid rafts formation. Br J Cancer. 2020;123(11):1673-1685. doi:https://doi.org/10.1038/s41416-020-01085-z

60.

Shearston

Tan

JTM

Cochran

, et al. Inhibition of vascular inflammation by apolipoprotein A-IV. Front Cardiovasc Med. 2022;9:901408. doi:https://doi.org/10.3389/fcvm.2022.901408

61.

Wang

Luo

Liu

, et al. Apolipoprotein M induces inhibition of inflammatory responses via the S1PR1 and DHCR24 pathways. Mol Med Rep. 2019;19(2):1272-1283. doi:https://doi.org/10.3892/mmr.2018.9747

62.

Zheng

Andersen

Rasmussen

, et al. Expression of genes and enzymes involved in ovarian steroidogenesis in relation to human follicular development. Front Endocrinol (Lausanne). 2023;14:1268248. doi:https://doi.org/10.3389/fendo.2023.1268248

63.

Zhang

Wang

, et al. Identification of DNA methylation-regulated genes as potential biomarkers for coronary heart disease via machine learning in the framingham heart study. Clin Epigenetics. 2022;14(1):122. doi:https://doi.org/10.1186/s13148-022-01343-2

64.

Drzewinska

Walczak-Drzewiecka

Ratajewski

. Identification and analysis of the promoter region of the human DHCR24 gene: Involvement of DNA methylation and histone acetylation. Mol Biol Rep. 2011;38(2):1091-1101. doi:https://doi.org/10.1007/s11033-010-0206-z

65.

Simi

Malentacchi

Luciani

, et al. Seladin-1 expression is regulated by promoter methylation in adrenal cancer. BMC Cancer. 2010;10:201. doi:https://doi.org/10.1186/1471-2407-10-201

66.

Song

Wang

. The role of N6-methyladenosine methylation in the progression of endometrial cancer. Cancer Biother Radiopharm. 2022;37(9):737-749. doi:https://doi.org/10.1089/cbr.2020.3912

67.

Meng

Zhang

Wang

, et al. Editorial: Efficacy and mechanism of herbal medicines and their functional compounds in preventing and treating cardiovascular diseases and cardiovascular disease risk factors. Front Pharmacol. 2023;14:1236821. doi:https://doi.org/10.3389/fphar.2023.1236821

68.

Walker

Vaher

Bermingham

, et al. Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles. Genome Med. 2021;13(1):1. doi:https://doi.org/10.1186/s13073-020-00808-4

69.

Ochoa-Rosales

Portilla-Fernandez

Nano

. Epigenetic link between statin therapy and type 2 diabetes. Diabetes Care. 2020;43(4):875-884. doi:https://doi.org/10.2337/dc19-1828

70.

Juvinao-Quintero

Sharp

. Investigating causality in the association between DNA methylation and type 2 diabetes using bidirectional two-sample Mendelian randomisation. Diabetologia. 2023;66(7):1247-1259. doi:https://doi.org/10.1007/s00125-023-05914-7

71.

Schrader

Perfilyev

. Statin therapy is associated with epigenetic modifications in individuals with type 2 diabetes. Epigenomics. 2021;13(12):919-925. doi:https://doi.org/10.2217/epi-2020-0442

72.

Braun

KVE

Dhana

de Vries

, et al. Epigenome-wide association study (EWAS) on lipids: The rotterdam study. Clin Epigenetics. 2017;9:15. doi:https://doi.org/10.1186/s13148-016-0304-4

73.

Dhana

Braun

KVE

Nano

, et al. An epigenome-wide association study of obesity-related traits. Am J Epidemiol. 2018;187(8):1662-1669. doi:https://doi.org/10.1093/aje

74.

Zaghlool

Mook-Kanamori

Kader

, et al. Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation. Hum Mol Genet. 2018;27(6):1106-1121. doi:https://doi.org/10.1093/hmg/ddy006

75.

Dekkers

van Iterson

Slieker

, et al. Blood lipids influence DNA methylation in circulating cells. Genome Biol. 2016;17(1):138. doi:https://doi.org/10.1186/s13059-016-1000-6

76.

Kazmi

Gaunt

Relton

, et al. Maternal eating disorders affect offspring cord blood DNA methylation: A prospective study. Clin Epigenetics. 2017;9:120. doi:https://doi.org/10.1186/s13148-017-0418-3

77.

Salem

Saito

Kasama

, et al. Genomic polymorphisms in 3β-hydroxysterol Δ24-reductase promoter sequences. Microbiol Immunol. 2013;57(3):179-184. doi:https://doi.org/10.1111/1348-0421.12025

78.

Dai

Zhu

Liu

, et al. Cholesterol synthetase DHCR24 induced by insulin aggravates cancer invasion and progesterone resistance in endometrial carcinoma. Sci Rep. 2017;7:41404. doi:https://doi.org/10.1038/srep41404

79.

Shen

, et al. TGF-β1 suppresses de novo cholesterol biosynthesis in granulosa-lutein cells by down-regulating DHCR24 expression via the GSK-3β/EZH2/H3K27me3 signaling pathway. Int J Biol Macromol. 2023;224:1118-1128. doi:https://doi.org/10.1016/j.ijbiomac.2022.10.196

80.

Zhang

Xin

, et al. Time-restricted feeding downregulates cholesterol biosynthesis program via RORγ-mediated chromatin modification in porcine liver organoids. J Anim Sci Biotechnol. 2020;11(1):106. doi:https://doi.org/10.1186/s40104-020-00511-9

81.

Zong

Zhao

, et al. Sodium butyrate alleviates deoxynivalenol-induced hepatic cholesterol metabolic dysfunction via RORγ-mediated histone acetylation modification in weaning piglets. J Anim Sci Biotechnol. 2022;13(1):133. doi:https://doi.org/10.1186/s40104-022-00793-1

82.

Zhang

Wang

Meng

, et al. A novel SRSF3 inhibitor, SFI003, exerts anticancer activity against colorectal cancer by modulating the SRSF3/DHCR24/ROS axis. Cell Death Discov. 2022;8(1):238. doi:https://doi.org/10.1038/s41420-022-01039-9

83.

Nelson

Clegg

Arnold

, et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci U S A. 2002;99(18):11890-11895. doi:https://doi.org/10.1073/pnas.182376299

84.

Benvenuti

Luciani

Vannelli

, et al. Estrogen and selective estrogen receptor modulators exert neuroprotective effects and stimulate the expression of selective Alzheimer's disease indicator-1, a recently discovered antiapoptotic gene, in human neuroblast long-term cell cultures. J Clin Endocrinol Metab. 2005;90(3):1775-1782. doi:https://doi.org/10.1210/jc.2004-0066

85.

Bonaccorsi

Luciani

Nesi

, et al. Androgen receptor regulation of the seladin-1/DHCR24 gene: Altered expression in prostate cancer. Lab Invest. 2008;88(10):1049-1056. doi:https://doi.org/10.1038/labinvest.2008.80

86.

Luciani

Deledda

Rosati

, et al. Seladin-1 is a fundamental mediator of the neuroprotective effects of estrogen in human neuroblast long-term cell cultures. Endocrinology. 2008;149(9):4256-4266. doi:https://doi.org/10.1210/en.2007-1795

87.

Zhang

, et al. Testosterone up-regulates seladin-1 expression by iAR and PI3-K/Akt signaling pathway in C6 cells. Neurosci Lett. 2012;514(1):122-126. doi:https://doi.org/10.1016/j.neulet.2012.02.072

88.

Peri

Danza

Benvenuti

, et al. New insights on the neuroprotective role of sterols and sex steroids: The seladin-1/DHCR24 paradigm. Front Neuroendocrinol. 2009;30(2):119-129. doi:https://doi.org/10.1016/j.yfrne.2009.03.006

89.

Dong

Zhang

Gao

, et al. Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer-specific biomarkers. Mol Cancer Ther. 2005;4(7):1047-1055. doi:https://doi.org/10.1158/1535-7163.MCT-05-0124

90.

Biancolella

Valentini

Minella

, et al. Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs. 2007;25(5):491-497. doi:https://doi.org/10.1007/s10637-007-9070-7

91.

Battista

Guimond

Roberge

, et al. Inhibition of DHCR24/seladin-1 impairs cellular homeostasis in prostate cancer. Prostate. 2010;70(9):921-933. doi:https://doi.org/10.1002/pros.21126

92.

Romanuik

Wang

Morozova

, et al. LNCap atlas: Gene expression associated with in vivo progression to castration-recurrent prostate cancer. BMC Med Genomics. 2010;3:43. doi:https://doi.org/10.1186/1755-8794-3-43

93.

Hwang

Lin

Shih

, et al. Pro-cellular survival and neuroprotection of citrus flavonoid: The actions of hesperetin in PC12 cells. Food Funct. 2012;3(10):1082-1090. doi:https://doi.org/10.1039/c2fo30100h

94.

Jiang

Wang

, et al. Evolution, expression profile, regulatory mechanism, and functional verification of EBP-like gene in cholesterol biosynthetic process in chickens (gallus gallus). Front Genet. 2020;11:587546. doi:https://doi.org/10.3389/fgene.2020.587546

95.

Heemers

Verhoeven

Swinnen

. Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. Mol Endocrinol. 2006;20(10):2265-2277. doi:https://doi.org/10.1210/me.2005-0479

96.

Guo

Ahmed

Zhang

, et al. Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat Genet. 2016;48(10):1142-1150. doi:https://doi.org/10.1038/ng.3637

97.

Bonucci

Gragnani

Trincado

, et al. The role of vitamin C in the gene expression of oxidative stress markers in fibroblasts from burn patients. Acta Cir Bras. 2018;33(8):703-712. doi:https://doi.org/10.1590/s0102-865020180080000006

98.

Yavuz

Alaylıoğlu

Şengül

, et al. Protein disulfide isomerase A3 might be involved in the regulation of 24-dehydrocholesterol reductase via vitamin D equilibrium in primary cortical neurons. In Vitro Cell Dev Biol Anim. 2021;57(7):704-714. doi:https://doi.org/10.1007/s11626-021-00602-5

99.

Lyu

Wang

Kang

, et al. RNA-Seq Reveals Sub-Zones in Mouse Adrenal Zona Fasciculata and the Sexually Dimorphic Responses to Thyroid Hormone. Endocrinology. 2020;161(9):bqaa126. doi:https://doi.org/10.1210/endocr/bqaa126

100.

Zheng

Kang

Lyu

, et al. DHCR24, a Key Enzyme of Cholesterol Synthesis, Serves as a Marker Gene of the Mouse Adrenal Gland Inner Cortex. Int J Mol Sci. 2023;24(2):933. doi:https://doi.org/10.3390/ijms24020933

101.

Jiang

102.

Fang

Jiang

Liu

, et al. Circ_0002099 is a novel molecular therapeutic target for bladder cancer. Drug Dev Res. 2022;83(8):1890-1905. doi:https://doi.org/10.1002/ddr.22005

103.

Jing

Hui

. Circular RNA_0033596 aggravates endothelial cell injury induced by oxidized low-density lipoprotein via microRNA-217-5p /chloride intracellular channel 4 axis. Bioengineered. 2022;13(2):3410-3421. doi:https://doi.org/10.1080/21655979.2022.2027062

104.

Liu

Wang

, et al. The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition. Mol Cancer. 2022;21(1):198. doi:https://doi.org/10.1186/s12943-022-01653-2

105.

Wang

Yang

, et al. The circROBO1/KLF5/FUS feedback loop regulates the liver metastasis of breast cancer by inhibiting the selective autophagy of afadin. Mol Cancer. 2022;21(1):29. doi:https://doi.org/10.1186/s12943-022-01498-9

106.

Yan

Zhang

, et al. LncRNA ENST00000370438 promotes cell proliferation by upregulating DHCR24 in breast cancer. Mol Carcinog. 2023;62(6):855-865. doi:https://doi.org/10.1002/mc.23529

107.

Frutos

Pardo-Marqués

Torrecilla-Parra

, et al. “MiR-7 controls cholesterol biosynthesis through posttranscriptional regulation of DHCR24 expression”. Biochim Biophys Acta Gene Regul Mech. 2023;1866(2):194938. doi:https://doi.org/10.1016/j.bbagrm.2023.194938

108.

Han

Chen

, et al. MicroRNA-124 regulates cardiomyocyte apoptosis and myocardial infarction through targeting Dhcr24. J Mol Cell Cardiol. 2019;132:178-188. doi:https://doi.org/10.1016/j.yjmcc.2019.05.007

109.

Liu

Hao

Wang

, et al. Identification of novel molecules and pathways associated with fascin actin-bundling protein 1 in laryngeal squamous cell carcinoma through comprehensive transcriptome analysis. Int J Mol Med. 2024;53(4):39. doi:https://doi.org/10.3892/ijmm.2024.5363

110.

Castillejo-López

Bárcenas-Walls

Cavalli

, et al. A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells. Lipids Health Dis. 2024;23(1):48. doi:https://doi.org/10.1186/s12944-024-02029-9

111.

Ohta-Shimizu

Fuwa

Tomitsuka

, et al. New inhibitory effect of latilactobacillus sakei UONUMA on the cholesterol biosynthesis pathway in human HepG2 cells. Biol Pharm Bull. 2021;44(4):485-493. doi:https://doi.org/10.1248/bpb.b20-00663

112.

Sansone

Galasso

Orefice

, et al. The green microalga tetraselmis suecica reduces oxidative stress and induces repairing mechanisms in human cells. Sci Rep. 2017;7:41215. doi:https://doi.org/10.1038/srep41215

113.

Wang

Liu

, et al. Obesity-induced overexpression of miRNA-24 regulates cholesterol uptake and lipid metabolism by targeting SR-B1. Gene. 2018;668:196-203. doi:https://doi.org/10.1016/j.gene.2018.05.072

114.

Harashima

Yamazaki

Motomura

, et al. Phenotype-genotype correlation in aldosterone-producing adenomas characterized by intracellular cholesterol metabolism. J Steroid Biochem Mol Biol. 2022;221:106116. doi:https://doi.org/10.1016/j.jsbmb.2022.106116

115.

Fuller

Alexiadis

Jobling

, et al. Seladin-1/DHCR24 expression in normal ovary, ovarian epithelial and granulosa tumours. Clin Endocrinol (Oxf). 2005;63(1):111-115. doi:https://doi.org/10.1111/j.1365-2265.2005.02308.x

116.

Ezzikouri

Kimura

Sunagozaka

, et al. Serum DHCR24 auto-antibody as a new biomarker for progression of hepatitis C. EBioMedicine. 2015;2(6):604-612. doi:https://doi.org/10.1016/j.ebiom.2015.04.007

117.

Chan

. Development of Serum DHCR24 antibody as a marker for hepatocellular carcinoma: The End of the beginning. EBioMedicine. 2015;2(6):497-498. doi:https://doi.org/10.1016/j.ebiom.2015.05.020

118.

Frances

Sharma

Pofahl

, et al. A role for Rac1 activity in malignant progression of sebaceous skin tumors. Oncogene. 2015;34(43):5505-5512. doi:https://doi.org/10.1038/onc.2014.471

119.

Romanuik

Ueda

, et al. Novel biomarkers for prostate cancer including noncoding transcripts. Am J Pathol. 2009;175(6):2264-2276. doi:https://doi.org/10.2353/ajpath.2009.080868

120.

Dai

Adachi

. In-depth proteomics reveals the characteristic developmental profiles of early lung adenocarcinoma with epidermal growth factor receptor mutation. Cancer Med. 2023;12(9):10755-10767. doi:https://doi.org/10.1002/cam4.5766

121.

Lee

Jung

, et al. DHCR24 Is an independent predictor of progression in patients with non-muscle-invasive urothelial carcinoma, and its functional role is involved in the aggressive properties of urothelial carcinoma cells. Ann Surg Oncol. 2014;21(Suppl 4):S538-S545. doi:https://doi.org/10.1245/s10434-014-3560-6

122.

Liu

Yin

Meng

, et al. DHCR24 Predicts poor clinicopathological features of patients with bladder cancer: A STROBE-compliant study. Medicine (Baltimore). 2018;97(39):e11830. doi:https://doi.org/10.1097/MD.0000000000011830

123.

Qiu

Cao

Chen

, et al. 24-Dehydrocholesterol Reductase promotes the growth of breast cancer stem-like cells through the hedgehog pathway. Cancer Sci. 2020;111(10):3653-3664. doi:https://doi.org/10.1111/cas.14587

124.

Nuti

Luciani

Marinari

, et al. Seladin-1 and testicular germ cell tumours: New insights into cisplatin responsiveness. J Pathol. 2009;219(4):491-500. doi:https://doi.org/10.1002/path.2622

125.

Dufresne

Bowden

Thavarajah

, et al. The plasma peptides of ovarian cancer. Clin Proteomics. 2018;15:41. doi:https://doi.org/10.1186/s12014-018-9215-z

126.

Pflugfelder

Yong

XLH

. Genome-wide association study suggests the variant rs7551288*A within the DHCR24 gene is associated with poor overall survival in melanoma patients. Cancers (Basel). 2022;14(10):2410. doi:https://doi.org/10.3390/cancers14102410

127.

Gunda

Genaro-Mattos

Kaushal

. Ubiquitous aberration in cholesterol metabolism across pancreatic ductal adenocarcinoma. Metabolites. 2022;12(1):47. doi:https://doi.org/10.3390/metabo12010047

128.

Mollinedo

Gajate

. Lipid rafts as major platforms for signaling regulation in cancer. Adv Biol Regul. 2015;57:130-146. doi:https://doi.org/10.1016/j.jbior.2014.10.003

129.

Wang

Che

, et al. Targeting CRABP-II overcomes pancreatic cancer drug resistance by reversing lipid raft cholesterol accumulation and AKT survival signaling. J Exp Clin Cancer Res. 2022;41(1):88. doi:https://doi.org/10.1186/s13046-022-02261-0

130.

Fei

Yan

, et al. Perturbing plasma membrane lipid: A new paradigm for tumor nanotherapeutics. Theranostics. 2023;13(8):2471-2491. doi:https://doi.org/10.7150/thno.82189

131.

Cecchi

Rosati

Pensalfini

, et al. Seladin-1/DHCR24 protects neuroblastoma cells against abeta toxicity by increasing membrane cholesterol content. J Cell Mol Med. 2008;12(5b):1990-2002. doi:https://doi.org/10.1111/j.1582-4934.2008.00216.x

132.

Chen

Weng

Huang

, et al. Anticancer peptide Q7 suppresses the growth and migration of human endometrial cancer by inhibiting DHCR24 expression and modulating the AKT-mediated pathway. Int J Med Sci. 2022;19(14):2008-2021. doi:https://doi.org/10.7150/ijms.78349

133.

Garnett

. Caveolae as a target to quench autoinduction of the metastatic phenotype in lung cancer. J Cancer Res Clin Oncol. 2016;142(3):611-618. doi:https://doi.org/10.1007/s00432-015-2074-3

134.

Schaefer

Guerra

. Protein kinase CK2 regulates redox homeostasis through NF-κB and bcl-xL in cardiomyoblasts. Mol Cell Biochem. 2017;436(1-2):137-150. doi:https://doi.org/10.1007/s11010-017-3085-y

135.

Khoi

Yin

, et al. Sulforaphane suppresses the nicotine-induced expression of the matrix metalloproteinase-9 via inhibiting ROS-mediated AP-1 and NF-κB signaling in human gastric cancer cells. int J Mol Sci. 2022;23(9):5172. doi:https://doi.org/10.3390/ijms23095172

136.

Lee

Fenster

Ito

, et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem. 1999;274(12):7936-7940. doi:https://doi.org/10.1074/jbc.274.12.7936

137.

Chang

Liu

Cao

, et al. Novel microtubule inhibitor SQ overcomes multidrug resistance in MCF-7/ADR cells by inhibiting BCRP function and mediating apoptosis. Toxicol Appl Pharmacol. 2022;436:115883. doi:https://doi.org/10.1016/j.taap.2022.115883

138.

Zhou

, et al. Pimozide inhibits the growth of breast cancer cells by alleviating the Warburg effect through the P53 signaling pathway. Biomed Pharmacother. 2022;150:113063. doi:https://doi.org/10.1016/j.biopha.2022.113063

139.

Nishimura

Kohara

Izumi

, et al. Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase. J Biol Chem. 2009;284(52):36442-36452. doi:https://doi.org/10.1074/jbc.M109.043232

140.

Ershov

Kaluzhskiy

. Enzymes in the cholesterol synthesis pathway: interactomics in the cancer context. Biomedicines. 2021;9(8):895. doi:https://doi.org/10.3390/biomedicines9080895

141.

Roeder

. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell. 1997;90(4):595-606. doi:https://doi.org/10.1016/s0092-8674(00)80521-8

142.

Ito

Lai

Zhao

, et al. P300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J. 2001;20(6):1331-1340. doi:https://doi.org/10.1093/emboj/20.6.1331

143.

Pan

Hong

Ren

. Reactive oxygen species: A double-edged sword in oncogenesis. World J Gastroenterol. 2009;15(14):1702-1707. doi:https://doi.org/10.3748/wjg.15.1702

144.

Kirtonia

Sethi

. The multifaceted role of reactive oxygen species in tumorigenesis. Cell Mol Life Sci. 2020;77(22):4459-4483. doi:https://doi.org/10.1007/s00018-020-03536-5

145.

Chibaya

Karim

Zhang

, et al. Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis. Proc Natl Acad Sci U S A. 2021;118(4):e2003193118. doi:https://doi.org/10.1073/pnas.2003193118

146.

Kong

Yuan

Zhu

, et al. The suppression of prostate LNCaP cancer cells growth by selenium nanoparticles through akt/Mdm2/AR controlled apoptosis. Biomaterials. 2011;32(27):6515-6522. doi:https://doi.org/10.1016/j.biomaterials.2011.05.032

147.

Rebbani

Tsukiyama-Kohara

. HCV-Induced Oxidative stress: Battlefield-winning strategy. Oxid Med Cell Longev. 2016;2016:7425628. doi:https://doi.org/10.1155/2016/7425628

148.

Dong

Guan

Zhang

, et al. Dhcr24 activates the PI3 K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice. Animal Model Exp Med. 2018;1(1):40-52. doi:https://doi.org/10.1002/ame2.12007

149.

Luciani

Gelmini

Ferrante

, et al. Expression of the antiapoptotic gene seladin-1 and octreotide-induced apoptosis in growth hormone-secreting and nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 2005;90(11):6156-6161. doi:https://doi.org/10.1210/jc.2005-0633

150.

Liu

Huang

Hong

, et al. Isovalerylspiramycin I suppresses non-small cell lung carcinoma growth through ROS-mediated inhibition of PI3 K/AKT signaling pathway. Int J Biol Sci. 2022;18(9):3714-3730. doi:https://doi.org/10.7150/ijbs.69989

151.

Isoyama

Tamaki

Noguchi

, et al. Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3 K inhibitors. Cell Death Dis. 2023;14(2):169. doi:https://doi.org/10.1038/s41419-023-05690-7

152.

Yao

, et al. 24-Dehydrocholesterol Reductase alleviates oxidative damage-induced apoptosis in alveolar epithelial cells via regulating phosphatidylinositol-3-kinase/protein kinase B activation. Bioengineered. 2022;13(1):155-163. doi:https://doi.org/10.1080/21655979.2021.2011634

153.

Icard

Simula

Fournel

, et al. The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications. Drug Resist Updat. 2022;63:100852. doi:https://doi.org/10.1016/j.drup.2022.100852

154.

Chakraborty

Balan

Sabarwal

, et al. Metabolic reprogramming in renal cancer: Events of a metabolic disease. Biochim Biophys Acta Rev Cancer. 2021;1876(1):188559. doi:https://doi.org/10.1016/j.bbcan.2021.188559

155.

Yao

Zhang

, et al. Protective effect of DHT on apoptosis induced by U18666A via PI3 K/Akt signaling pathway in C6 glial cell lines. Cell Mol Neurobiol. 2016;36(5):801-809. doi:https://doi.org/10.1007/s10571-015-0263-x

156.

Hei

Liu

. Upregulation of seladin-1 and nestin expression in bone marrow mesenchymal stem cell transplantation via the ERK1/2 and PI3 K/Akt signaling pathways in an Alzheimer's disease model. Oncol Lett. 2018;15(5):7443-7449. doi:https://doi.org/10.3892/ol.2017.7543

157.

Chen

Choi

Wen

, et al. A p53-phosphoinositide signalosome regulates nuclear AKT activation. Nat Cell Biol. 2022;24(7):1099-1113. doi:https://doi.org/10.1038/s41556-022-00949-1

158.

Nie

Zou

Meng

, et al. Bioactive iridium nanoclusters with glutathione depletion ability for enhanced sonodynamic-triggered ferroptosis-like cancer cell death. Adv Mater. 2022;34(45):e2206286. doi:https://doi.org/10.1002/adma.202206286

159.

Dong

Zhao

, et al. Anti-apoptotic HAX-1 suppresses cell apoptosis by promoting c-abl kinase-involved ROS clearance. Cell Death Dis. 2022;13(4):298. doi:https://doi.org/10.1038/s41419-022-04748-2

160.

Ren

Wang

Weng

, et al. Multifaceted role of redox pattern in the tumor immune microenvironment regarding autophagy and apoptosis. Mol Cancer. 2023;22(1):130. doi:https://doi.org/10.1186/s12943-023-01831-w

161.

Pellegrini

De Martino

. Blockage of autophagosome-lysosome fusion through SNAP29 O-GlcNAcylation promotes apoptosis via ROS production. Autophagy. 2023;19(7):2078-2093. doi:https://doi.org/10.1080/15548627.2023.2170962

162.

Deng

Fan

, et al. Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells. Biochem Pharmacol. 2018;148:64-74. doi:https://doi.org/10.1016/j.bcp.2017.12.004

163.

Saito

Takano

Nishimura

, et al. 3β-hydroxysterol δ24-reductase on the surface of hepatitis C virus-related hepatocellular carcinoma cells can be a target for molecular targeting therapy. PLoS One. 2015;10(4):e0124197. doi:https://doi.org/10.1371/journal.pone.0124197

164.

Higgs

Chouteau

Lerat

. ‘Liver let die': Oxidative DNA damage and hepatotropic viruses. J Gen Virol. 2014;95(Pt 5):991-1004. doi:https://doi.org/10.1099/vir.0.059485-0

165.

Di Stasi

Vallacchi

Campi

, et al. DHCR24 Gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress-induced apoptosis. Int J Cancer. 2005;115(2):224-230. doi:https://doi.org/10.1002/ijc.20885

166.

Hendriksen

Dits

Kokame

, et al. Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res. 2006;66(10):5012-5020. doi:https://doi.org/10.1158/0008-5472.CAN-05-3082

167.

Kotawong

Chajaroenkul

Roytrakul

, et al. The proteomics and metabolomics analysis for screening the molecular targets of action of β-eudesmol in cholangiocarcinoma. Asian Pac J Cancer Prev. 2021;22(3):909-918. doi:https://doi.org/10.31557/APJCP.2021.22.3.909

168.

Qin

Wang

Pedersen

, et al. Dynamic patterns of blood lipids and DNA methylation in response to statin therapy. Clin Epigenetics. 2022;14(1):153. doi:https://doi.org/10.1186/s13148-022-01375-8

169.

Ramos

Sierra

Ramirez

, et al. Simvastatin modulates the Alzheimer's disease-related gene seladin-1. J Alzheimers Dis. 2012;28(2):297-301. doi:https://doi.org/10.3233/JAD-2011-111118

170.

Hernández-Jiménez

Martínez-López

Gabandé-Rodríguez

, et al. Seladin-1/DHCR24 is neuroprotective by associating EAAT2 glutamate transporter to lipid rafts in experimental stroke. Stroke. 2016;47(1):206-213. doi:https://doi.org/10.1161/STROKEAHA.115.010810

171.

Wang

, et al. Virtual Screening of Novel 24-Dehydroxysterol Reductase (DHCR24) Inhibitors and the Biological Evaluation of Irbesartan in Cholesterol-Lowering Effect. Molecules. 2023;28(6):2643. doi:https://doi.org/10.3390/molecules28062643

172.

Yuan

Yong

Zhu

, et al. DPP4 Regulates DHCR24-mediated cholesterol biosynthesis to promote methotrexate resistance in gestational trophoblastic neoplastic cells. Front Oncol. 2021;11:704024. doi:https://doi.org/10.3389/fonc.2021.704024

173.

Sung

Ferlay

Siegel

, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi:https://doi.org/10.3322/caac.21660

174.

Wang

, et al. National and subnational trends in cancer burden in China, 2005-20: An analysis of national mortality surveillance data. Lancet Public Health. 2023;8(12):e943-e955. doi:https://doi.org/10.1016/S2468-2667(23)00211-6

175.

Kini

Vengrenyuk

Shameer

, et al. Intracoronary imaging, cholesterol efflux, and transcriptomes after intensive statin treatment: The YELLOW II study. J Am Coll Cardiol. 2017;69(6):628-640. doi:https://doi.org/10.1016/j.jacc.2016.10.029

176.

Liu

Yao

. DHCR24 Overexpression modulates microglia polarization and inflammatory response via Akt/GSK3β signaling in aβ(25)(-)(35) treated BV-2 cells. Life Sci. 2020;260:118470. doi:https://doi.org/10.1016/j.lfs.2020.118470

177.

Luo

, et al. A prognostic model of seven immune genes to predict overall survival in childhood acute myeloid leukemia. Biomed Res Int. 2022;2022:7724220. doi:https://doi.org/10.1155/2022/7724220

178.

Simonen

Chua

, et al. Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase. J Intern Med. 2020;288(5):560-569. doi:https://doi.org/10.1111/joim.13095

179.

Allen

Genaro-Mattos

Anderson

, et al. Amiodarone alters cholesterol biosynthesis through tissue-dependent inhibition of emopamil binding protein and dehydrocholesterol reductase 24. ACS Chem Neurosci. 2020;11(10):1413-1423. doi:https://doi.org/10.1021/acschemneuro.0c00042

180.

Yang

Zhao

, et al. Agomelatine prevents amyloid plaque deposition, tau phosphorylation, and neuroinflammation in APP/PS1 mice. Front Aging Neurosci. 2021;13:766410. doi:https://doi.org/10.3389/fnagi.2021.766410

181.

Dincer

Yildiztekin

Cinar

. Unlocking synergistic potential: Agomelatine enhances the chemotherapeutic effect of paclitaxel in breast cancer cell through MT1 melatonin receptors and ER-alpha axis. Chem Biodivers. 2023;20(10):e202301093. doi:https://doi.org/10.1002/cbdv.202301093

182.

Moreno-SanJuan

Puentes-Pardo

Casado

, et al. Agomelatine, a Melatonin-Derived Drug, as a New Strategy for the Treatment of Colorectal Cancer. Antioxidants (Basel). 2023;12(4):926. doi:https://doi.org/10.3390/antiox12040926

183.

Hassanzadeh

Hosseini

Pasbakhsh

, et al. Trimetazidine prevents oxidative changes induced in a rat model of sporadic type of Alzheimer's disease. Acta Med Iran. 2015;53(1):17-24. PMID: 25597600.

184.

Peng

Jin

, et al. Inhibition of ACAA1 restrains proliferation and potentiates the response to CDK4/6 inhibitors in triple-negative breast cancer. Cancer Res. 2023;83(10):1711-1724. doi:https://doi.org/10.1158/0008-5472.CAN-22-2143

185.

Zhou

Xie

Hou

, et al. Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the hippo/YAP1/c-jun axis. J Exp Clin Cancer Res. 2023;42(1):111. doi:https://doi.org/10.1186/s13046-023-02671-8

186.

Brånvall

Ekberg

Eloranta

, et al. Statin use is associated with improved survival in multiple myeloma: A Swedish population-based study of 4315 patients. Am J Hematol. 2020;95(6):652-661. doi:https://doi.org/10.1002/ajh.25778

187.

Cardwell

Hicks

Hughes

, et al. Statin use after colorectal cancer diagnosis and survival: A population-based cohort study. J Clin Oncol. 2014;32(28):3177-3183. doi:https://doi.org/10.1200/JCO.2013.54.4569

188.

Abdel-Rahman

. Statin treatment and outcomes of metastatic pancreatic cancer: A pooled analysis of two phase III studies. Clin Transl Oncol. 2019;21(6):810-816. doi:https://doi.org/10.1007/s12094-018-1992-3

189.

Lee

, et al. Randomized phase II study of Afatinib plus simvastatin versus Afatinib alone in previously treated patients with advanced nonadenocarcinomatous non-small cell lung cancer. Cancer Res Treat. 2017;49(4):1001-1011. doi:https://doi.org/10.4143/crt.2016.546

190.

Han

Lee

Yoo

, et al. A randomized phase II study of gefitinib plus simvastatin versus gefitinib alone in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2011;17(6):1553-1560. doi:https://doi.org/10.1158/1078-0432.CCR-10-2525

191.

Kim

Kang

Lee

, et al. Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: A double-blind randomised phase 3 study. Eur J Cancer. 2014;50(16):2822-2830. doi:https://doi.org/10.1016/j.ejca.2014.08.005

192.

Trindade

Ceglia

Berthelette

, et al. The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation. Immunity. 2021;54(10):2273-2287.e6. doi:https://doi.org/10.1016/j.immuni.2021.09.004

193.

Huang

, et al. Cholesterol negatively regulates IL-9-producing CD8(+) T cell differentiation and antitumor activity. J Exp Med. 2018;215(6):1555-1569. doi:https://doi.org/10.1084/jem.20171576

194.

Buchwald

. Cholesterol inhibition, cancer, and chemotherapy. Lancet. 1992;339(8802):1154-1156. doi:https://doi.org/10.1016/0140-6736(92)90744-n

195.

Huang

Song

. Cholesterol metabolism in cancer: Mechanisms and therapeutic opportunities. Nat Metab. 2020;2(2):132-141. doi:https://doi.org/10.1038/s42255-020-0174-0

196.

Kuzu

Noory

Robertson

. The role of cholesterol in cancer. Cancer Res. 2016;76(8):2063-2070. doi:https://doi.org/10.1158/0008-5472.CAN-15-2613