FTO attenuates the cytotoxicity of cisplatin on KGN cells by regulating the Hippo/YAP1 signaling pathway

Abstract

Premature ovarian failure (POF) is a devastating condition for women under 40 years old. Chemotherapy, especially the cisplatin, has been demonstrated to promote the apoptosis of granulosa cell in primary and secondary follicle, and then leading to POF. Our previous studies have demonstrated that fat mass- and obesity-associated (FTO) plays an essential role in protecting granulosa cells from cisplatin-induced cytotoxicity. Various studies have suggested that the Hippo/YAP signaling pathway plays a significant role in regulating cell apoptosis and proliferation. And YAP1 was the main downstream target of Hippo signaling pathway, which was negatively regulated by Hippo signaling pathway. However, whether the Hippo/YAP signaling pathway is involved in the protective effect of FTO on granulosa cells remains unclear. In this study, we found that, after cisplatin treatment, the apoptosis of granulosa cells increased in a concentration-dependent manner, accompanied by the downregulation of FTO and YAP1. Furthermore, overexpression of FTO decreased cisplatin induced granulosa cell apoptosis, inhibited the Hippo/YAP kinase cascade induced phosphorylation of YAP1, and promoted the entry of YAP1 into the nuclei. The downstream targets of YAP1 (CTGF, CYR61, and ANKRD1) were also increased. Si-RNA mediated down-regulation of FTO promoted cisplatin induced granulosa cells apoptosis, activated the Hippo/YAP kinase cascade, and inhibited the YAP1 entry into nuclei. And these effects were completely reversed by the small molecule inhibitor of YAP1-verteporfin (VP). Co-ip assay showed that there was a strong interaction between proteins of FTO and YAP1.Taken together, these data suggested that FTO-YAP1 played a positive role in regulated injured granulosa cells proliferation, induced by cisplatin.