The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis

Coiled-coil domain containing 6 (CCDC6) is a tumour suppressor gene involved in apoptosis and DNA damage response. CCDC6 is known to be functionally impaired upon gene fusions, somatic mutations, and altered protein turnover in several tumours. Testicular germ cell tumours are among the most common...

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Autores principales:	Francesco Morra, Francesco Merolla, Federica Zito Marino, Rosaria Catalano, Renato Franco, Paolo Chieffi, Angela Celetti
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Seminoma Embryonal carcinoma DNA DSBs Homologous recombination PARP inhibitors Deferoxamine Science (General) Q1-390 Social sciences (General) H1-99
Acceso en línea:	https://doaj.org/article/1febab4fea964416bdfa82e956fce2cc
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spelling	oai:doaj.org-article:1febab4fea964416bdfa82e956fce2cc2021-12-02T05:03:02ZThe tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis2405-844010.1016/j.heliyon.2021.e08399https://doaj.org/article/1febab4fea964416bdfa82e956fce2cc2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2405844021025020https://doaj.org/toc/2405-8440Coiled-coil domain containing 6 (CCDC6) is a tumour suppressor gene involved in apoptosis and DNA damage response. CCDC6 is known to be functionally impaired upon gene fusions, somatic mutations, and altered protein turnover in several tumours. Testicular germ cell tumours are among the most common malignancies in young males. Despite the high cure rate, achieved through chemotherapy and/or surgery, drug resistance can still occur. In a human cellular model of testis Embryonal Carcinoma, the deficiency of CCDC6 was associated with defects in DNA repair via homologous recombination and sensitivity to PARP1/2 inhibitors. Same data were obtained in a panel of murine testicular cell lines, including Sertoli, Spermatogonia and Spermatocytes. In these cells, upon oxidative damage exposure, the absence of CCDC6 conferred tolerance to reactive oxygen species affecting regulated cell death pathways by apoptosis and ferroptosis. At molecular level, the loss of CCDC6 was associated with an enhancement of the xCT/SLC7A11 cystine antiporter expression which, by promoting the accumulation of ROS, interfered with the activation of ferroptosis pathway. In conclusion, our data suggest that the CCDC6 downregulation could aid the testis germ cells to be part of a pro-survival pathway that helps to evade the toxic effects of endogenous oxidants contributing to testicular neoplastic growth. Novel therapeutic options will be discussed.Francesco MorraFrancesco MerollaFederica Zito MarinoRosaria CatalanoRenato FrancoPaolo ChieffiAngela CelettiElsevierarticleSeminomaEmbryonal carcinomaDNA DSBsHomologous recombinationPARP inhibitorsDeferoxamineScience (General)Q1-390Social sciences (General)H1-99ENHeliyon, Vol 7, Iss 11, Pp e08399- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Seminoma Embryonal carcinoma DNA DSBs Homologous recombination PARP inhibitors Deferoxamine Science (General) Q1-390 Social sciences (General) H1-99
spellingShingle	Seminoma Embryonal carcinoma DNA DSBs Homologous recombination PARP inhibitors Deferoxamine Science (General) Q1-390 Social sciences (General) H1-99 Francesco Morra Francesco Merolla Federica Zito Marino Rosaria Catalano Renato Franco Paolo Chieffi Angela Celetti The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
description	Coiled-coil domain containing 6 (CCDC6) is a tumour suppressor gene involved in apoptosis and DNA damage response. CCDC6 is known to be functionally impaired upon gene fusions, somatic mutations, and altered protein turnover in several tumours. Testicular germ cell tumours are among the most common malignancies in young males. Despite the high cure rate, achieved through chemotherapy and/or surgery, drug resistance can still occur. In a human cellular model of testis Embryonal Carcinoma, the deficiency of CCDC6 was associated with defects in DNA repair via homologous recombination and sensitivity to PARP1/2 inhibitors. Same data were obtained in a panel of murine testicular cell lines, including Sertoli, Spermatogonia and Spermatocytes. In these cells, upon oxidative damage exposure, the absence of CCDC6 conferred tolerance to reactive oxygen species affecting regulated cell death pathways by apoptosis and ferroptosis. At molecular level, the loss of CCDC6 was associated with an enhancement of the xCT/SLC7A11 cystine antiporter expression which, by promoting the accumulation of ROS, interfered with the activation of ferroptosis pathway. In conclusion, our data suggest that the CCDC6 downregulation could aid the testis germ cells to be part of a pro-survival pathway that helps to evade the toxic effects of endogenous oxidants contributing to testicular neoplastic growth. Novel therapeutic options will be discussed.
format	article
author	Francesco Morra Francesco Merolla Federica Zito Marino Rosaria Catalano Renato Franco Paolo Chieffi Angela Celetti
author_facet	Francesco Morra Francesco Merolla Federica Zito Marino Rosaria Catalano Renato Franco Paolo Chieffi Angela Celetti
author_sort	Francesco Morra
title	The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
title_short	The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
title_full	The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
title_fullStr	The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
title_full_unstemmed	The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
title_sort	tumour suppressor ccdc6 is involved in ros tolerance and neoplastic transformation by evading ferroptosis
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/1febab4fea964416bdfa82e956fce2cc
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The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis

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