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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

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DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review

Abstract

Keywords

Introduction

Name Determination

Structure of DHCR24 Gene and DHCR24

DHCR24 Catalyzes Cholesterol Synthesis

Regulation of DHCR24 Gene Expression

Metabolites or Metabolite Analogues Regulate Gene Expression

Structure of DHCR24 Gene Affects its Expression

Hormones Affect DHCR24 Gene Expression

Non-Coding RNA Affects DHCR24 Gene Expression

Other Regulatory Mechanisms of DHCR24 Expression

The Value of DHCR24 in the Diagnosis and Treatment of Tumors

DHCR24 Is Used as a Biomarker for Tumor Diagnosis

Mechanisms of DHCR24 Promotes Tumor Progression

DHCR24 Is a Potential Target for Tumor Therapy

Cancer Therapy Targeting DHCR24 is Becoming a Reality

Summary and Prospect

Conclusion

Footnotes

Acknowledgements

Authors’ Contributions:

Declaration of Conflicting Interests

Funding

ORCID iD

References