头颈鳞癌中胆固醇合成代谢重编程影响癌蛋白EZH2抑制剂敏感性的机制研究

异常高表达的组蛋白甲基转移酶EZH2与头颈鳞癌的癌前转化和恶性表型维持密切相关，是公认的重要抗肿瘤靶标。但单独使用EZH2抑制剂对头颈鳞癌的治疗效果有待提高，尚缺乏从肿瘤代谢角度分析影响EZH2抑制剂敏感性的机制及药物合用方案。我们前期研究证实EZH2抑制剂处理后，头颈鳞癌细胞胆固醇合成途径代谢酶表达增强，推测胆固醇代谢重编程影响了细胞对EZH2抑制剂的敏感性。本研究拟分析EZH2抑制剂对头颈肿瘤细胞的表观遗传学和非靶向代谢组，筛选并验证代谢中间产物对EZH2抑制剂敏感性的影响；确定能与EZH2抑制剂协同抑制肿瘤生长的临床药物组合；利用胆固醇合成中间产物角鲨烯构建新型聚合物胶束，以增加EZH2抑制剂的药物溶解性和抑瘤效果。本研究的重要意义在于揭示EZH2直接改变肿瘤胆固醇代谢重编程的调控方式；研究结果将为开发EZH2抑制剂的新药物组合和和新型载药系统提供实验基础。

EZH2, a highly expressed histone methyltransferase, is closely related to the precancerous transformation and the maintenance of malignant phenotype of head and neck squamous cell carcinoma, and is recognized as an important anti-tumor target. However, the therapeutic effect of EZH2 inhibitor alone on head and neck squamous cell carcinoma needs to be improved. The mechanism of affecting EZH2 inhibitor sensitivity and drug combination scheme are still lacking from the perspective of tumor metabolism. Our previous studies have confirmed that EZH2 inhibitors in head and neck cancer cells can improve the enzymes expression in the de novo synthesis of endogenous cholesterol. We hypotheses that metabolic reprogramming of cholesterol synthesis can affect the sensitivity of head and neck cancer cells to EZH2 inhibitors. The purpose of this study is to analyze the epigenetic and non -targeted metabolomics of EZH2 inhibitors on head and neck cancer cells, and to screen and verify the effect of metabolic intermediates on the sensitivity of EZH2 inhibitors; Finally, we will find the clinical drug combination that can cooperate with EZH2 inhibitor to inhibit tumor growth.