头颈鳞癌中甲基转移酶EZH2催化STAT1蛋白甲基化促进PD-L1表达和功能的机制研究

EZH2被认为是头颈鳞癌中一个具有重要促癌作用的组蛋白甲基转移酶，通过调控染色体空间构象影响靶基因表达。然而目前尚缺少研究EZH2对组蛋白以外的其他蛋白质进行翻译后甲基化修饰。本项目组在前期开发了一类特殊作用模式的EZH2抑制剂，能特异而有效地诱导EZH2降解，是关闭EZH2功能的有力工具。在药理作用研究的过程中，我们发现EZH2可能催化了STAT1的一个赖氨酸残基甲基化修饰，直接影响STAT1的转录活性和靶基因PD-L1的表达。本研究将结合分析化学、分子生物学、细胞生物学和实验动物学的研究手段，分析EZH2甲基化STAT1的时间和空间机制；阐述EZH2对头颈鳞癌细胞PD-L1表达的影响和逃避免疫细胞杀伤的机制。本研究的重要意义在于发现一种EZH2直接改变STAT1活性的调控方式，揭示一条信号通路；研究结果将为开发EZH2抑制剂的新药物组合和治疗策略提供实验和理论基础。

EZH2 has been identified as an important oncoprotein and methyltransferase in head and neck squamous cancer. The protein is broadly considered as a key drug target. However, the research on other functions of EZH2 is limited and few targets have been found in post-translational levels. Our previously developed a unique EZH2 inhibitor to degrade EZH2 protein. During the pharmalogical experiments, we found a new modification of STAT1 and EZH2 catalyze the specific methylation. According to the critical role of STAT1 on PD-L1 expression and escaping immune cytotoxity, we plan to perform comprehensive study on the mechanism. In this application, we will study the direct influence of EZH2-induced STAT1 methylation and the PD-L1 related mechanism. This study will significantly extend the field of novel EZH2 inhibitor and find the new combination to treat cancers.