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

Francesco Morra,Francesco Merolla,Federica Zito Marino,Rosaria Catalano,Renato Franco,Paolo Chieffi,Angela Celetti

doi:10.1016/j.heliyon.2021.e08399

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.

Highlights

Testicular germ cell tumours (TGCTs) represent one of the most common malignancies in young men [1]
Appreciable levels of Coiled-coil domain containing 6 (CCDC6) and USP7 proteins were detected in NTERA-2 human Embryonal Carcinoma and in the murine GC-1 spermatogonia cells, while nearly undetectable amount was observed in GC-2 spermatocytes and TM4 Sertoli cells (Fig. 1 E)
In order to assess the efficacy of homologous recombination (HR) repair, the murine testicular cells and the human NTERA-2 Embryonal Carcinoma (EC) cells, left untreated or following pretreatment with P5091, depending on the CCDC6 expression levels, were transfected with the DR-GFP reporter plasmid alone, as a control, or together with the I-SceI plasmid, able to induce double strand break (DSB)

Summary

Introduction

Testicular germ cell tumours (TGCTs) represent one of the most common malignancies in young men [1]. TGCTs are divided into pure seminoma and nonseminomatous germ cell tumours [2], which include embryonal cell carcinoma, choriocarcinoma, yolk sac tumour and teratoma. The death or survival of the different populations of the testis depends on the balance between survival and regulated cell death signals in response to reactive oxygen species. Among the regulated cell death programmes, ferroptosis has been recently characterized as an iron- and lipid reactive oxygen species (ROS)dependent form of death, distinct from other patterns of regulatory cell death at the morphological, biological, and genetic levels [3, 4]. Ferroptosis can be inhibited in different cancer types and may function as a dynamic tumour suppressor in cancer development, suggesting that the regulation of ferroptosis can be utilized as an interventional target for tumour treatment [6]

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