Abstract
Cancer, a deadly disease is characterized by abnormal cell growth with the potential to invade to other parts of the body. Most cancers start due to changes at gene level that happen over a person’s lifetime when DNA repair system becomes faulty. CCDC6, one of the players in DNA repair system acts as a tumor suppressor gene. It was originally identified in chimeric genes caused by chromosomal translocation involving RET proto-oncogene in some thyroid tumors. Different fusion chimers with different proto-oncogenes like RET are known for CCDC6 which hampered its function. Further, CCDC6 is recognized as a pro-apoptotic phosphoprotein, which is an ATM substrate responsive to genotoxic stress. In this article, we reviewed the published literature to characterize CCDC6 fusions with proto-oncogenes and the role of natural phytochemicals which can potentially alter CCDC6 activity and thus can prove beneficial for cancer patients.
Introduction
CCDC6 gene encodes for Coiled-coil domain containing 6 protein, which is known to be a tumor suppressor gene, involved in apoptosis and DNA damage response [1]. It was originally identified in chimeric genes caused by fusion of CCDC6 with RET [receptor tyrosine kinase] by chromosomal paracentral inversion of the right arm of chromosome of RET. This leads to the chimeric oncogene PTC1 which is responsible for Papillary Thyroid Carcinoma on exposure to ionizing radiations [2, 3]. Alternative titles for this gene are H4, D10S170, Transforming Sequence Thyroid 1 [TST1], single copy probe pH4, PTC, TPC.
Earlier CCDC6 was considered as a partner of RET [Receptor tyrosine] alone to which it provides its promoter and first 101 amino acids required for continuous activation of tyrosine kinase domain of RET which is located at carboxyl terminus. But whether it remains partner of RET alone or it also forms fusion protein with other oncogenes remain mystery for long time. It was reported that CCDC6 forms fusion with RET in 20% of papillary thyroid carcinoma in humans on exposure to ionizing radiations [4, 5]. High frequency of CCDC6/RET fusion was due to spatial arrangement of locus of two genes in thyroid cell’s nucleus. These two loci were identified as hot spots of recombination via an in-vitro experiment [6]. Although, in transgenic mice having CCDC6/RET fusion, it was found that tumors other than thyroid also occur. This suggests that CCDC6/RET has role in development of other tumors too [7].
Fusion of CCDC6 with different oncogenes along with their cytogenetic location [information retrieved from http://atlasgeneticsoncology. org/Genes/H4ID280.html ]
Fusion of CCDC6 with different oncogenes along with their cytogenetic location [information retrieved from
Earlier it was reported that fusion of CCDC6/RET occurs in other tumors also like adenocarcinoma of lung and colorectal cancer in humans [8, 9, 10, 11]. The result is summarized in Fig. 1. It had been found that loss of CCDC6 activity leads to oncogenic activity by compromising DNA damage repair and reducing apoptotic process. However, with the advancements in research and bioinformatics tools, an exponential growth in the number of protooncogenes which binds to CCDC6, resulting into different types of cancer, were reported (Table 1) [12, 13, 14].
The various cellular functions of CCDC6.
Thus it is observed that CCDC6 is involved in forming fusion proteins with different protooncogenes [which otherwise have normal role in cell proliferation], which strengthens the role of CCDC6 in development of cancer and its progression [15].
CCDC6 gene is located on long arm of chromosome 10 [10q21], and contains 9 exons that encode a transcript of 3 Kb showing an open reading frame [ORF] of 475 amino acids. The CCDC6 gene promoter is localized within 259 base pairs upstream of the translation initiation site ATG [16, 17]. A CCDC6 is a 3 Kb transcript which is highly conserved and is ubiquitously expressed in human tissues [1]. CCDC6 protein is 475 amino acids long and contains an extensive region of alpha helices which have high potential to adopt coiled coil conformation [17]. Coiled-coils are formed from two or three alpha helices that are strongly amphipathic and super coil around each other, crossing at an angle of about 20
CCDC6 is a phosphoprotein, which is a target for many S/T kinases which regulate the protein stability and movement into the nucleus on receiving various cellular signals from ERK1/2, ATM [Ataxia telangactasia mutase], CDK1/2 [cyclin-dependent kinase] [20, 21, 1]. The main function of CCDC6 is in providing apoptotic response, mediated by ATM for DNA damage. When the cell is exposed to genotoxic stress, ATM kinase becomes active and phosphorylates CCDC6 at threonine 434, thus stabilizing CCDC6 in nucleus, while in ATM defective cells, the CCDC6 remains inside the cytoplasm or gets out of the nucleus and CCDC6 does not get phosphorylated. Inhibition of ATM kinase due to some reasons even after having enough ATM, interferes with CCDC6 apoptotic activity. Moreover, if CCDC6 gets mutated somehow by replacing threonine 434 with alanine, this excludes CCDC6 from nucleus and saves the cell from apoptotic process [21]. Mammalian cell which is silenced for CCDC6 activity survives easily after DNA damage and proceeds into mitosis [3]. It was found that those cells which have attenuated CCDC6, does not exhibit S-phase accumulation on exposure to etoposide [22]. So it was observed that in the absence of CCDC6, when genotoxic stress like irradiation exposure or etoposide affects cells, they repair the damaged DNA by Non homologous end joining [NHEJ] instead of homologous recombination [which takes place when CCDC6 is active]. NHEJ is an error prone process. Down regulation of CCDC6 is associated with less amount of Rad51, which is a DNA repair foci and leads to reduced response to DNA damage [3].
The mechanism which is responsible for this effect is that CCDC6 acts as negative regulator of PP4c [phosphatase], which dephosphorylates H2AX [histone H2A] on S139. This results in reduction of Rad51 [DNA Damage Response foci], and ultimately leads to overcoming of G2 arrest which is essential for proper DNA repair. Moreover the phosphorylation of CHK1 [checkpoint kinase 1], which is a sign of activated cellular checkpoint, is not there when CCDC6 is absent [3]. Hence cells which have either less or inactive CCDC6 does not have ability to recognize DNA repair checkpoint and proceed further into mitosis which leads to cancer development. In addition to this S-phase checkpoint CDC25 phosphatase [which is otherwise present in cytoplasm upon genotoxic stress], is also not present in cytoplasm in absence of CCDC6 [22]. Cells which lack CCDC6 show downregulation of 14-3-3 sigma, which is a major cell cycle regulator. This shows that CCDC6 causes cancer possibly by creating disturbances in cell cycle regulation [23]. Moreover, low levels of tumor suppressor transcript EWS is revealed, which promotes apoptosis in CCDC6 dependent manner [24, 25] (Fig. 2).
The various molecular effects of lack of CCDC6.
Levels of CCDC6 protein vary on change in phase of cell cycle or on stress induction. Its level and phosphorylation status undergoes cyclic variation as it increases in G2 phase of cell cycle and decreases in mitosis [26, 24, 25]. The amount of CCDC6 inside the cell, changes due to post transcriptional modifications instead of transcription [27, 28, 25]. The stability of CCDC6 is reduced in M phase due to mitotic kinases and presence of degron motifs in CCDC6 which recruits E3 ubiquitin ligase on CCDC6. E3 ubiquitin ligase Fbxw7 degrades CCDC6 by ubiquitin mediated proteasomal degradation [28]. When DNA damage happens then E3 ubiquitin mediated CCDC6 degradation is stopped. Mechanically, during DNA damage response, CCDC6 gets phosphorylated at Thr434 by ATM kinase. This prevents interaction of E3 ubiquitin ligase Fbxw7 and CCDC6 and hence degradation of CCDC6 [28]. Intracellular level of CCDC6 is stabilized by USP7 and thus amount of CCDC6 depends upon Fbxw7 and USP7 activity [25]. Researchers have shown that CCDC6 forms complex with proteins which bind to DNA. CCDC6 binds to CREB1 which is a transcription factor, and regulates transcription of those proteins which are involved in cell proliferation [29]. CCDC6 decreases transcriptional activity of CREB1, in SUMO2 dependent manner, with the help of histone deacetylase1 and protein phosphatase1 [PP1] at CRE site of CREB1 target genes [28, 29].
Cancer is a disease which involves abnormal cell growth that can invade to other body parts [Cancer fact sheet, WHO, 2010]. It is second leading cause of death in the world after cardiovascular diseases. Today, many cancer patients life is prolonged by early identification and treatment of disease [30]. There are several causes of cancer which include: sunlight, tobacco, pharmaceuticals, hormones, alcohol, parasites, fungi, bacteria, salted fish, wood dust, herbs, red meat, processed meats, low fibre diets, not breast feeding, obesity, increased adult height and sedentary lifestyles [31]. Despite of all these causes there are some genes which are involved in development of cancer namely protooncogenes and tumor suppressor genes. Protooncogenes are generally involved in cell growth which is regulated by tumor suppressor genes, but any disturbance in this natural process of cell growth and cell cycle, results in cancer. American Cancer Society, every year estimates new cases and deaths in United States. In 2017, 1,688,780 new cases and 600,920 cancer deaths are found in America. For all sites, the cancer incidence rate and cancer death rate is 20% higher in men than in women [32].
Role of CCDC6 in causing cancer becomes evident when it gets fused with different oncogenes. The structures that are present in CCDC6 itself help in the progression of cancer, as coiled coil domain of CCDC6 gives hydrophobic surface for oligomerization of CCDC6 [33, 18], and 101 amino acids of CCDC6 which are involved in the fusion with different oncogenes acts as dominant negative signal for presence of CCDC6 full length protein inside the nucleus [34]. For CCDC6, to work efficiently as tumor suppressor, it must be inside the nucleus. If somehow it comes out of the nucleus then it cannot do its work which leads to cancer.
It was found that CCDC6 knock-in mice developed thyroid hyperplasia, which shows increased CREB1 activity and expression of CREB1 regulated genes [35, 49]. This evidence supports involvement of CCDC6 in development of cancer. RET/CCDC6 fusion results not only in papillary thyroid carcinoma but also adenocarcinoma of lung and colorectal cancer in humans [15]. However, fusion of CCDC6 is also reported with many oncogenes other than RET, which results into different kinds of cancer (Table 1). Thus, it can be said that either lack or fusion of CCDC6, or its exclusion from nucleus is associated with cancer [15]. Weak staining of CCDC6 protein in IHC analysis is significantly related with lymph node metastasis while negatively related with disease free survival and overall survival in Non-small cell lung cancer [25, 37]. Recently found that, patients of lung cancer who exhibit resistance for EGFR [Epidermal growth factor receptor] tyrosine kinase inhibitors, also show activation of CCDC6-RET in those samples in which cancer was already developed [38]. Furthermore, repression of CREB1 [cAMP response element binding protein 1] activity by CCDC6, with the help of histone deacetylase and protein phosphatase 1, has a major role in the development of papillary thyroid carcinoma [29].
It was also found that there is a critical role of CCDC6 in the development of testicular germ cell tumors. CCDC6 helps in the DNA damage response by acting as a substrate of ATM kinase. DNA damage response, which is crucial for saving cell from cancer, is almost absent in testicular germ cell tumors because of absence of CCDC6 in the spermatogonial cells [39]. CCDC6 was expressed at very low levels in 30% of Non-small cell lung cancer, which is the main cause of the disease; though it is also found fused with RET in some cases. Due to less expression of CCDC6, DNA repair by homologous recombination in double strand breaks, becomes severely affected [37].
Fusions of CCDC6 with different oncogene in different cancers
Fusion of CCDC6 with RET
RET is a receptor tyrosine kinase which takes part in the growth of neural crest derived cell lineage, kidney and male germ cells. N-terminal of coiled coil domain of CCDC6 helps in dimerization of RET domain, which results in the constitutive activation of tyrosine kinase of RET in the absence of ligands [40]. Fusion of CCDC6 with RET leads to different types of cancer like papillary and thyroid carcinoma, lung adenocarcinoma and colorectal cancer [15, 41]. Approximately 1% of RET fusions are found in lung cancer [41]. CCDC6-RET expressed endogenously contribute to cell growth but RET inhibitors decrease cell viability and are used as an effective treatment for cancers caused by CCDC6-RET fusion [8]. As there are mutations in the structure of RET, it acts as a good target for cancer treatment [40].
Fusion of CCDC6 with PDGFRB
PDGFRB stands for Platelet derived growth factor receptor beta. It functions as a tyrosine protein kinase that acts as cell surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB and plays an essential role in regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and blood vessel development by promoting proliferation, migration and recruitment of pericytes and smooth muscle cells to endothelial cells. Fusion of CCDC6 and PDGFRB causes BCR-ABL negative chronic myeloid leukemia. Very few cases are reported for this fusion. CCDC6 is present at 10q21 and PDGFRB is present at 5q32 and has 25 exons. This fusion is done by t[5; 10] [q33; q21] translocation, which is a cytogenetic problem that happens in BCR-ABL negative myeloproliferative neoplasms [12]. Knock out mice phenotype has shown that PDGFRB is necessary for vascular development. Deletion of PDGFRB decreases pericytes and vascular smooth muscle cells and thus disturbs the structure/function of vasculature in brain, heart, kidney, eye and skin [42, 43, 44, 45]. The abnormal protein of CCDC6 and PDGFRB contains first 368 amino acids including part of coiled coil domain of CCDC6 and the leucine zipper of H4 and the entire tyrosine kinase domain and transmembrane domain of PDGFRB. Activation of PDGFRB needs de-repession of kinase activity of receptor. Activated receptor gets phosphorylated and becomes involved in intracellular signaling pathway which starts cellular response like migration and cell proliferation. Mutations in the kinase domain result in constitutive activation of PDGFRB causing cancerous growth [46, 47].
Fusion of CCDC6 with KITLG
KITLG stands for KIT Ligand. This gene encodes the ligand of the tyrosine kinase receptor encoded by the KIT locus. This ligand is a pleiotropic factor that acts in utero in germ cell and neural cell development and hematopoiesis, all believed to reflect a role in cell migration. In adults, it functions pleiotropically, while mostly noted for its continued requirement in hematopoiesis. Fusion of CCDC6 and KITLG results in adenocarcinoma of lung. KITLG gene codes for ligand of the tyrosine-kinase receptor which is encoded by the KIT locus.
This ligand is a pleiotropic factor that acts in development of germ cell and neural cell. It is continuously required for hematopoiesis, all these functions have prominent role in cell proliferation and migration [48]. It has important role in the regulation of cell survival and proliferation. It is also required for hematopoiesis, maintenance of stem cell, generation of gametes, development of mast cell etc. KITLG/SCF binding is capable of activating many signaling pathways. It helps in phosphorylating PIK3R1, which is a regulatory subunit of phosphatidylinositol 3-kinase, and these results in activation of the kinase AKT1 interleukins. It also transmits signals via GRB2 and activates RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1 [Uniprot].
Fusion of CCDC6 with FGFR2
FGFR2 stands for fibroblast growth factor receptor 2. It is a receptor tyrosine kinase which becomes activated when FGF ligand binds on it. This further activates RAS-MAPK and PI3K-AKT signaling pathways. In cancer FGFR2 functions get altered which results in increased cell growth and decreased apoptosis [49]. Fusion of CCDC6 and FGFR2 results in cholangiocarcinoma, breast cancer and prostate cancer. FGFR2-CCDC6 fusion induces oligomerization which ultimately activates FGFR kinase activity and increases cell growth [35]. Up to 13% of intrahepatic cholangiocarcinoma are due to presence of FGFR2 fusion proteins. FGFR fusions can be considered as druggable target for cancer. Tumors which have FGFR fusions have shown increased sensitivity for FGFR inhibitors, which suggests that patients of cholangiocarcinoma who will have FGFR2 fusions, may get treated by targeted FGFR2 kinase inhibition [50]. In a study in which mouse xenograft model was used, which had CCDC6-FGFR2 fusion protein from metastatic lung nodule of intrahepatic cholangiocarcinoma patient, it was established that FGFR inhibitors, Ponatinib, Dovitinib and BJG398 have capability to change FGFR signaling, stops cell growth and induce cell apoptosis. However, BGJ398 was found more superior than Ponatinib and Dovitinib. Thus, these findings have given very strong rationale for more research on FGFR inhibitors mainly BGJ398 as a treatment option for cholangiocarcinoma patient having FGFR2 fusions [50].
Fusion of CCDC6 with ANK3
ANK3 stands for Ankyrin 3, also known as ankyrin G. ANK3-CCDC6 fusions are reported in 1% of tumors associated with epithelial ovarian cancer and 2 out of 1140 in breast cancer [51]. Ankyrin-3 [ANK-3] is a protein from ankyrin family that is encoded by the ANK3 in humans [52]. This gene encodes proteins which are immunologically distinct from other ankyrins and are present in axonal initial segment and node of ranvier in neurons of central and peripheral nervous system [53]. In nodes of ranvier, where action potentials are actively propagated, ankyrin G is thought to bind to neurofascin and voltage gated sodium channels [54]. ANK3 protein connects integral membrane proteins which are present below spectrin-actin cytoskeleton. Ankyrins have major role in cell movement, activation, growth, contact and it maintains some specific membrane domains. Mostly Ankyrins have three structural domains: an amino terminal domain which has multiple ankyrin repeats, a central region which is a conserved spectrin binding domain and a carboxy terminal which is a regulatory domain and subjected to variation.
Fusion of CCDC6 with LIPI
LIPI stands for Lipase1. This gene has 10 exons and spans more than 100 Kb. It is mapped at 21q11.2, centromeric to the STCH gene [55]. Cytogenetic location of fusion of CCDC6 and LIPI is t[10; 21] [q21; q11]. This fusion was found to cause Non small cell lung cancer. The protein encoded by LIPI gene is a phospholipase which breaks down phosphatidic acid to give lysophosphatidic acid [a potent bioactive lipid mediator]. This gene is highly expressed in Ewing family tumor cells. LIPI is a cancer antigen and studies show that it may act as potential drug target [56].
Fusion of CCDC6 with CTNNA3
CTNNA3 stands for Catenin alpha 3. Fusion of CTNNA3 and CCDC6 causes Non small cell lung cancer. CTNNA3 gene is mapped to chromosome 10q21 [57]. CTNNA3 is a cell adhesion molecule. It encodes a protein of vinculin/alpha-catenin family. This protein helps in linking of cadherin and actin containing filament of cytoskeleton or in cell-cell adhesion of muscle cells [58]. Knockdown of CTNNA3 in Schwann cells showed cytoskeletal problems and less E-Cadherin expression resulting into epithelial-mesenchymal transition like abnormalities. Thus CTNNA3 can also be considered as a novel tumor suppressor gene [59]. Transfection of CTNNA3 in alpha-catenin deficient colon carcinoma cells used E-cadherin and beta-catenin at cell junctions and restored cell-cell adhesion. CTNNA3 is essential for buildup of cell adhesion complexes in muscle cells [60]. Human CTNNA3 gene has 18 exons and spread into about 1,776 kb. The exon-exon boundaries of CTNNA3 both in human and mouse are conserved. However, introns of CTNNA3, both in human and mouse are very large [more than 100 kb] [57].
Fusion of CCDC6 with ROS1
ROS is ROS protooncogene 1, functions as growth or differentiation factor receptor. Fusion of CCDC6 and ROS1 causes Non small cell lung cancer. ROS1 is a receptor tyrosine kinase that undergoes genetic rearrangements in different cancers which includes glioblastoma, colorectal, ovarian, non small cell lung cancer, gastric adenocarcinoma, angiosarcoma, myofibroblastic tumor. In these cancers ROS1 gets rearranged and forms fusion proteins in which kinase domain becomes constitutively active which leads to cell proliferation [61]. Inhibiting the kinase activity of fusion protein is a promising strategy for treating non small cell lung cancer [62, 63].
Fusion of CCDC6 with PTEN
PTEN stands for Phosphatase and Tensin homolog [64]. It acts as a tumor suppressor gene by the help of its phosphatase protein product [65]. Fusion of CCDC6 and PTEN involves t[10; 10] [q21; q23] and causes thyroid cancer. PTEN is mapped on chromosome 10q22-23 encodes for phosphatase which has dual-specificity. Reduced PTEN expression is found in thyroid cancer development. Characterization of rearrangements at chromosome 10 during fusion of CCDC6 and PTEN is done by Puxeddu et al. The initial CCDC6/PTEN fusion was found as a non-specific product of RT-PCR in irradiated thyroid cell lines for RET/PTC1, but later sequencing showed a transcript which has exon 1 and 2 of CCDC6, fused with exon 3–6 of PTEN. Confirmation of H4/PTEN rearrangements in irradiated Kat1 and Kat50 cells was done by nested PCR with specific primers. Their formation was confirmed by presence of reciprocal H4/PTEN product. 28% of H4/PTEN products were found in normal thyroid tissues while 78% were found in papillary thyroid carcinoma by nested PCR [66].
Fusion of CCDC6 with VPS13B
VPS13B [Vacuolar protein sorting 13 homolog B] present at [8; 10] [q22; q21] forms fusion protein with CCDC6 present at [10; q21] by translocation and results in papillary thyroid carcinoma [67, 68]. VPS13B encodes a transmembrane protein that may function in vesicle mediated transport and sorting of protein inside the cell. It is a very big protein which is found associated with Golgi apparatus. It has 3997 amino acids. Mutation in VPS13B causes Cohen syndrome. Its depletion causes disruption of normal Golgi organization [69]. Moreover, protein glycosylation is also found defective, which is a major function of Golgi bodies [70]. VPS13B gene contains 62 exons and is spread in 864 kb.
Fusion of CCDC6 with other different proto-oncogenes
CCDC6 was also found to get fused with different proto-oncogenes which results in different types of cancer. Some examples like it was found to form fusion partners with UBE2D1, KCNH8, BRAF, RAD1 etc (Fig. 3). Mechanistically, very less is known about actual effect of CCDC6 fusions with these proto-oncogenes, further research is required in depth for this.
The different proto-oncogenic fusion partners of CCDC6.
Presence of CCDC6 influences genome stability. Cells which lack CCDC6 acts as BRCA defective cells, which possess resistance to chemotherapeutic agents and provide sensitivity to small molecule inhibitor of PARP1/2 [Poly ADP – ribose polymerase] [71]. BRCA defects induce synthetic lethality, which imparts PARP inhibition [72]. Intracellularly, when PARP enzymes are inhibited then single strand breaks in DNA cannot be repaired, which results into toxic double strand breaks, that are lethal in those cells which lack Homologous recombination repair or have lost repair genes [72, 73]. CCDC6 down regulation is associated with impairment of homologous recombination repair, which induces sensitivity to PARP inhibitors [1, 24].
In ovarian cancer also, there are homologous recombination [HR] DNA repair defects [because of BRCA1/2 mutations], as happens in lung cancer cells expressing low levels of CCDC6. FDA has approved OLAPARIB for treating cancer, which is an inhibitor of Poly ADP ribose polymerase [PARP] [74, 75]. Inhibition of PARP causes damage of base excision repair pathway, and eventually results into accumulation of single strand breaks, which become double strand breaks after getting replicated. In healthy cells as DNA repair pathways works perfectly so PARP inhibition is not of major consequence. But in BRCA mutated cancers in which HR repair and BER repair becomes compromised, and DSBs are accumulated then PARP inhibitors can effectively act to kill tumor cells [73]. So, as the loss of CCDC6 also causes defects in HR repair, it is demonstrated that Olaparib can also be used for treating lung cancer cells. Moreover, effects of Olaparib are increased when given along with cisplatinum [25]. So in Non small cell lung cancer in which CCDC6 expression is less, Olaparib can be given as first line platinum based chemotherapy. In 30% of NSCLC [Non small cell lung cancer], CCDC6 is down regulated so Olaparib can be used easily but for 70% of NSCLC in which CCDC6 levels are normal, a different therapeutic approach is proposed. Olaparib is ineffective on healthy cells but effective to cancer cells when given initially but after some time cancer cells develop resistance to it. The prerequisite thing for olaparib to work is CCDC6 should be down regulated. Then cancer cells will be sensitive to olaparib. Since for olaparib to act efficiently, levels of CCDC6 should be low. The level of CCDC6 can be controlled by E3 ubiquitin ligase Fbxw7, that addresses CCDC6 to proteasome degradation whereas deubiquitinase Usp7 stabilizes it [25]. Hence an inhibitor of Usp7, P5091 is used that lowers the level of CCDC6 and thus sensitize even those lung cancer cells which exhibit normal CCDC6 levels (Fig. 4). Researchers have proposed same therapy for patients of small cell lung cancer [76]. Hence CCDC6 is also considered as a biomarker for more personalized therapy. In cells bearing CCDC6/RET rearrangements, CCDC6 function is lost. So RET rearranged NSCLC will be sensitive to Olaparib alone or in combination of vandetanib [a novel tyrosine kinase inhibitor of RET] [25, 37, 38, 76, 71].
The various cellular modifiers of CCDC6.
In the same way, in Prostate cancer, CCDC6 attenuation provides sensitivity to Olaparib, irrespective of their castration status [71]. 30% of castration resistant prostate cancer patients have DNA repair gene mutations with which they can respond to PARP inhibitor treatment [77, 78]. Hence identification of CCDC6 as a predictive biomarker in different types of cancer can confer sensitivity to PARP inhibitor treatment for cancer. Thus data which is generated needs to go to clinicians so that information on levels of CCDC6 can be used in the treatment of patients [14, 79].
Involvement of CCDC6, in causing cancer is established, when its function is found lost either due to its down regulation or chromosomal rearrangements upon fusion with different proto-oncogene. In normal cells, CCDC6 plays a role of proapoptotic protein, identifying DNA damage checkpoints, maintaining genomic stability by homologous recombination, and ultimately proceeding for apoptosis if DNA repair cannot be done properly (Fig. 5). However, it is essential to scrutinize CCDC6 rearrangements in different cancers. More in depth research is required about actual role of CCDC6 and its fusions with different oncogenes. As CCDC6 defects provides resistance to conventional treatment and provide sensitivity to PARP inhibitors, which has been proved as a reliable treatment for time being. So, detection of CCDC6 impairment can be useful for treating cancer patients.
The various molecular functions of CCDC6.