Related Experiment Video
Updated: Oct 11, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis
Francesco Morra1, Francesco Merolla2, Federica Zito Marino3
1Institute for the Experimental Endocrinology and Oncology, Research National Council, CNR, Naples, Italy.
Abstract:
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.
Insights
Coiled-coil domain containing 6 (CCDC6) deficiency impairs DNA repair and promotes resistance to PARP1/2 inhibitors in testicular cancer cells. Loss of CCDC6 also confers tolerance to reactive oxygen species, impacting cell death pathways and potentially driving tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Coiled-coil domain containing 6 (CCDC6) is a tumor suppressor gene crucial for apoptosis and DNA damage response.
- CCDC6 dysfunction is implicated in various cancers, including testicular germ cell tumors (TGCTs).
- TGCTs are common in young males, and drug resistance remains a clinical challenge.
Purpose of the Study:
- To investigate the role of CCDC6 deficiency in testicular cancer.
- To explore the impact of CCDC6 loss on DNA repair, drug sensitivity, and cell death pathways.
- To elucidate the molecular mechanisms underlying CCDC6-mediated resistance to oxidative stress.
Main Methods:
- Utilized human embryonal carcinoma cells and murine testicular cell lines (Sertoli, Spermatogonia, Spermatocytes).
- Assessed DNA repair via homologous recombination and sensitivity to PARP1/2 inhibitors.
- Induced oxidative damage and analyzed cell death pathways (apoptosis, ferroptosis) and reactive oxygen species (ROS) accumulation.
Main Results:
- CCDC6 deficiency led to impaired homologous recombination and sensitivity to PARP1/2 inhibitors in testicular cancer models.
- Absence of CCDC6 conferred tolerance to ROS, affecting apoptosis and ferroptosis.
- Loss of CCDC6 correlated with enhanced xCT/SLC7A11 expression, promoting ROS accumulation and inhibiting ferroptosis.
Conclusions:
- CCDC6 downregulation may promote germ cell survival by evading oxidative stress, contributing to testicular cancer development.
- Altered CCDC6 expression presents potential therapeutic targets for testicular cancers.
- Further research into novel therapeutic strategies targeting CCDC6 pathways is warranted.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:23Abnormal Proliferation
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...