CCDC6 (coiled-coil domain containing 6)

Morra, Francesco; Miro, Caterina; Napolitano, Valeria; Merolla, Francesco; Celetti, Angela

doi:10.4267/2042/62666

Cited by 4 publications

(8 citation statements)

References 9 publications

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“…Coiled Coil Domain Containing 6 (CCDC6) gene product is ubiquitously expressed and target substrate of several serine/treonine kinases named ERK1/2, ATM, CDK1, and GSK3β, which, depending on the intracellular signaling, modulate the stability and the intracellular distribution of the protein [1][2][3][4][5][6][7]. In the nucleus CCDC6 exerts a main action in the process of DNA homologous recombination (HR) for the repair of DNA double strand breaks (DSB) and for the cell mitotic entry.…”

Section: Introductionmentioning

confidence: 99%

NSCLC Mutated Isoforms of CCDC6 Affect the Intracellular Distribution of the Wild Type Protein Promoting Cisplatinum Resistance and PARP Inhibitors Sensitivity in Lung Cancer Cells

Cerrato

Morra

Domenico

et al. 2019

Cancers

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CCDC6 is implicated in cell cycle checkpoints and DNA damage repair by homologous recombination (HR). In NSCLC, CCDC6 is barely expressed in about 30% of patients and CCDC6 gene rearrangements with RET and ROS kinases are detected in about 1% of patients. Recently, CCDC6 point-mutations naming E227K, S351Y, N394Y, and T462A have been identified in primary NSCLC.In this work, we analyze the effects exerted by the CCDC6 mutated isoforms on lung cancer cells. By pull-down experiments and immunofluorescence, we evaluated the biochemical and morphological effects of CCDC6 lung-mutants on the CCDC6 wild type protein. By using two HR-reporter assays, we analyzed the effect of CCDC6 lung-mutants in perturbing CCDC6 physiology in the HR process. Finally, by cell-titer assay, we evaluated the response to the treatment with different drugs in lung cancer cells expressing CCDC6 mutants. This work shows that the CCDC6 mutated and truncated isoforms, identified so far in NSCLC, affected the intracellular distribution of the wild type protein and impaired the CCDC6 function in the HR process, ultimately inducing cisplatinum resistance and PARP-inhibitors sensitivity in lung cancer cells. The identification of selected molecular alterations involving CCDC6 gene product might define predictive biomarkers for personalized treatment in NSCLC.Cancers 2020, 12, 44 2 of 18 exposed to DNA damage also decreases the levels of the G2-checkpoint phospho-protein Chk1 and shortens the G2 phase, allowing a premature entrance into the mitosis [9,10].Cancer cells carrying HR DNA repair molecular alteration, like BRCA1/2 defects, are selective target of the PARP inhibition, resulting in a synthetic lethal phenotype. Indeed, cancer cells defective for CCDC6 show an impaired HR process and switch to the non-homologous end joining process (NHEJ) to repair their DNA. As the NHEJ process is prone to errors, the cancer cells defective for CCDC6 show tolerance to the DNA damage induced by several mutagens, including cis-platinum. Furthermore, the switch to the NHEJ repair process that involves the poly (ADP-ribose) polymerase enzymes (PARP1/2) makes the CCDC6 defective cells sensitive to PARP inhibition because of a synthetic lethal effect [11].In several in vitro cancer cell systems CCDC6 protein levels have been correlated with cancer cell tolerance to DNA damage, resistance to cisplatinum and sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi) [4,[11][12][13][14][15][16].To date, besides the first CCDC6 fusion with the tyrosine kinase RET identified in papillary thyroid cancer [17,18], additional CCDC6 fusions have been reported with PDGFRb [19,20], PTEN [21], FGFR2 [22,23] ANK3 [24], and UBE2D1 [25] and with other genes in different tumor types [26].Following the fusions, the recombinant oncogenes always include, at least in part, the CCDC6 coiled-coil region that is able to induce protein dimers [27,28]. Interestingly, in the case of CCDC6/RET, the first 101 amminoacid (aa) of CCDC6 involved in the fusion can form heterodimers with wild...

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Section: Introductionmentioning

confidence: 99%

NSCLC Mutated Isoforms of CCDC6 Affect the Intracellular Distribution of the Wild Type Protein Promoting Cisplatinum Resistance and PARP Inhibitors Sensitivity in Lung Cancer Cells

Cerrato

Morra

Domenico

et al. 2019

Cancers

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“…In particular, CCDC6 gene product is involved in DNA damage and repair processes [ 17 – 19 ]. In primary tumors, the impaired function of CCDC6 protein has been ascribed to CCDC6 gene rearrangements or CCDC6 somatic mutations [ 20 – 21 ]. Moreover, altered levels of CCDC6 protein in cancer cells seem to depend on the altered turnover of CCDC6 protein regulated by the de-ubiquitinase USP7 [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells

et al. 2017

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Purpose of the studyReduced levels of the tumor suppressor protein CCDC6 sensitize cancer cells to the treatment with PARP-inhibitors. The turnover of CCDC6 protein is regulated by the de-ubiquitinase USP7, which also controls the androgen receptor (AR) stability. Here, we correlated the expression levels of CCDC6 and USP7 proteins in primary prostate cancers (PC). Moreover, we tested the efficacy of the USP7 inhibitors, in combination with PARP-inhibitors as a novel therapeutic option in advanced prostate cancer.Experimental techniquesPC cells were exposed to USP7 inhibitor, P5091, together with cycloheximide, to investigate the turnover of the USP7 substrates, AR and CCDC6. As outcome of the AR downregulation, transcription targets of AR and its variant V7 were examined by qPCR. As a result of CCDC6 degradation, the induction of PARP inhibitors sensitivity was evaluated by analyzing PC cells viability and foci formation. We scored and correlated CCDC6 and USP7 expression levels in a prostate cancer tissue microarray (TMA).ResultsP5091 accelerated the degradation of AR and V7 isoform affecting PSA, UBE2C, CDC20 transcription and PC cells proliferation. Moreover, P5091 accelerated the degradation of CCDC6 sensitizing the cells to PARP-inhibitors, that acted sinergistically with genotoxic agents. The immunohistochemical analysis of both CCDC6 and USP7 proteins exhibited significant correlation for the intensity of staining (p ≤ 0.05).Data interpretationThus, CCDC6 and USP7 represent predictive markers for the combined treatment of the USP7-inhibitors and PARP-inhibitors in advanced prostate cancer.

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“…The CCDC6 3 kb transcript (4401 bp) is highly conserved in the phylogeny and is expressed in almost all human tissues. 53 The CCDC6 transcript contains an open reading frame (ORF) of 475 amino acids with a start site that is localized to a region 2100 to 2190 (-144) bp of the translation initiation site (ATG). The CCDC6 promoter is located to a region within 259 bp upstream of the ATG site.…”

Section: Ccdc6 Structure and Functionsmentioning

confidence: 99%

“…The cDNA corresponding to the sequence of the gene, initially identified as H4(D10S170), was isolated from a human normal thyroid cDNA library and sequenced. The CCDC6 3 kb transcript (4401 bp) is highly conserved in the phylogeny and is expressed in almost all human tissues …”

Section: Introductionmentioning

confidence: 99%

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CCDC6: the identity of a protein known to be partner in fusion

Cerrato

Merolla

Morra

et al. 2017

Intl Journal of Cancer

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Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time, CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types. CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemoresistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect. Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments.

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CCDC6 (coiled-coil domain containing 6)

Cited by 4 publications

References 9 publications

NSCLC Mutated Isoforms of CCDC6 Affect the Intracellular Distribution of the Wild Type Protein Promoting Cisplatinum Resistance and PARP Inhibitors Sensitivity in Lung Cancer Cells

NSCLC Mutated Isoforms of CCDC6 Affect the Intracellular Distribution of the Wild Type Protein Promoting Cisplatinum Resistance and PARP Inhibitors Sensitivity in Lung Cancer Cells

The combined effect of USP7 inhibitors and PARP inhibitors in hormone-sensitive and castration-resistant prostate cancer cells

CCDC6: the identity of a protein known to be partner in fusion

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