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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605351/ https://www.ncbi.nlm.nih.gov/pubmed/34841108 http://dx.doi.org/10.1016/j.heliyon.2021.e08399 |
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author | Morra, Francesco Merolla, Francesco Zito Marino, Federica Catalano, Rosaria Franco, Renato Chieffi, Paolo Celetti, Angela |
author_facet | Morra, Francesco Merolla, Francesco Zito Marino, Federica Catalano, Rosaria Franco, Renato Chieffi, Paolo Celetti, Angela |
author_sort | Morra, Francesco |
collection | PubMed |
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 | Online Article Text |
id | pubmed-8605351 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-86053512021-11-26 The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis Morra, Francesco Merolla, Francesco Zito Marino, Federica Catalano, Rosaria Franco, Renato Chieffi, Paolo Celetti, Angela Heliyon Research Article 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. Elsevier 2021-11-15 /pmc/articles/PMC8605351/ /pubmed/34841108 http://dx.doi.org/10.1016/j.heliyon.2021.e08399 Text en © 2021 The Authors. Published by Elsevier Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Morra, Francesco Merolla, Francesco Zito Marino, Federica Catalano, Rosaria Franco, Renato Chieffi, Paolo Celetti, Angela The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605351/ https://www.ncbi.nlm.nih.gov/pubmed/34841108 http://dx.doi.org/10.1016/j.heliyon.2021.e08399 |
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