Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity

Leone, Vincenza; Langella, Carla; Esposito, Francesco; Arra, Claudio; Palma, Giuseppe; Rea, Domenica; Paciello, Orlando; Merolla, Francesco; Biase, Davide De; Papparella, Serenella; Celetti, Angela

doi:10.18632/oncotarget.3858

Cited by 22 publications

(24 citation statements)

References 23 publications

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“…The overall importance of the cell cycle checkpoints and DNA damage repair (DDR) proteins in maintaining genomic integrity is highlighted by the observation that the genes involved in the DDR process are often lost, mutated, or silenced in cancer cells [45][46][47][48][49]. Because of its role in the surveillance of DNA integrity, CCDC6 has been proposed as a tumor suppressor gene [4,50].…”

Section: Discussionmentioning

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: Discussionmentioning

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 has been identified as a negative regulator of CREB1 dependent transcription and tumours harboring the CCDC6-RET oncogene or occurring in Ccdc6-ex2 knock-in mice exhibit an enhanced phosphorylation and activity of CREB1 with a consequent increased expression of Amphiregulin (AREG) one of the known ligand for the EGFR family [ 100 , 119 , 120 ]. The autocrine production of Amphiregulin (AREG) is a parallel compensatory survival signaling responsible of “off-targets” TKIs resistance identified in different tumour types.…”

Section: Ccdc6/tk Fusions and Challenge Of Combined Therapy To Overcomentioning

confidence: 99%

The rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer

Cerrato¹,

Visconti²,

Celetti³

2018

Mol Cancer

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Gene fusions occur in up to 17% of solid tumours. Oncogenic kinases are often involved in such fusions. In lung cancer, almost 30% of patients carrying an activated oncogene show the fusion of a tyrosine kinase to an heterologous gene. Several genes are partner in the fusion with the three kinases ALK, ROS1 and RET in lung. The impaired function of the partner gene, in combination with the activation of the kinase, may alter the cell signaling and promote the cancer cell addiction to the oncogene. Moreover, the gene that is partner in the fusion to the kinase may affect the response to therapeutics and/or promote resistance in the cancer cells. Few genes are recurrent partners in tyrosine kinase fusions in lung cancer, including CCDC6, a recurrent partner in ROS1 and RET fusions, that can be selected as possible target for new strategies of combined therapy including TKi.

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“…This effect could promote cancer beside determining the homo‐dimerization and transforming ability of the fusion‐oncoprotein. Accordingly, Ccdc6‐ex2 knock‐in mice developed thyroid hyperplasia associated with an enhanced CREB1 activity and an increased expression of the CREB‐1 regulated genes . These evidences strongly support a proper role of CCDC6 impairment in promoting the tumor development.…”

Section: Introductionmentioning

confidence: 53%

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 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity

Cited by 22 publications

References 23 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 rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer

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

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