MED12通过Hippo-YAP通路调控卵巢癌细胞铁死亡敏感性的机制研究

化疗耐药是卵巢癌治疗失败的主要原因，亟需开发克服卵巢癌化疗耐药的新方法。前期我们已发表文章报道，MED12低表达卵巢癌细胞对化疗耐药（Cancer Research，2018）。近期预实验结果显示这部分化疗耐药细胞对铁死亡更敏感，其机制可能通过激活Hippo-YAP通路下游靶基因。据此我们提出假说：耐药相关分子MED12通过Hippo-YAP通路调控卵巢癌细胞铁死亡敏感性。本研究拟采用细胞和分子生物学实验，明确MED12通过Hippo-YAP通路调控铁死亡敏感性的功能；以ATAC-seq、ChIP-seq等方法，探究MED12调控Hippo-YAP通路的分子机理；以功能实验，蛋白表达检测结合相关性分析，明确卵巢癌临床样本中MED12与Hippo-YAP通路激活和铁死亡敏感性的相关性。本研究将阐明MED12调控卵巢癌细胞铁死亡敏感性的功能，机制和临床意义，为克服卵巢癌化疗耐药提供新策略。

Chemoresistance is the leading cause of treatment failure of ovarian cancer, and it is urgent to develop new methods to overcome chemoresistance of ovarian cancer. Previously, we have published that MED12 lower expression ovarian cancer cells were resistant to chemotherapy (cancer research, 2018). Our recent preliminary results showed that these chemoresistant cells were more sensitive to ferroptosis, which may be mediated by activating the downstream target genes of Hippo-YAP pathway. We hypothesized that chemoresistance related MED12 regulated ferroptosis sensitivity of ovarian cancer cells through Hippo-YAP pathway. We will use cell and molecular biology experiments to clarify the function of MED12 in regulating ferroptosis sensitivity through Hippo-YAP pathway. We will use ATAC-Seq and ChIP-seq and so on to explore the molecular mechanism that MED12 regulates Hippo-YAP pathway. We will use functional experiments, protein expression detection and correlation analysis to analysis the correlations between MED12 and Hippo-YAP pathway activation and ferroptosis sensitivity in ovarian cancer clinical samples. This study will clarify the function, mechanism and clinical significance of MED12 in regulating the sensitivity of ferroptosis in ovarian cancer cells, and provide a new strategy for overcoming chemoresistance of ovarian cancer.