结直肠癌奥沙利铂耐药是导致治疗失败、预后不良的重要原因。脂肪酸代谢异常被发现与化疗耐药密切相关。申请者前期研究提示ERCC2和SREBP1形成功能复合体，调控脂肪酸代谢关键基因FASN，增强脂肪酸合成代谢，可能是结直肠癌奥沙利铂耐药新的重要机制。为了进一步证明上述假设，阐明具体机制，我们将采用免疫荧光、共沉淀和GST-pull-down方法验证ERCC2和SREBP1相互结合；CHIP/RE-CHIP、荧光素酶报告基因实验证实ERCC2/SREBP1靶向富集于FASN启动子区域，激活FASN表达；基因干预和人体组织样本验证ERCC2/SREBP1-FASN对结直肠癌脂肪酸合成代谢和奥沙利铂耐药的调控作用。本项目首次提出脂肪酸合成代谢在结直肠癌奥沙利铂耐药中的关键作用，探索了ERCC2/SREBP1-FASN通路在结直肠癌脂肪酸合成和奥沙利铂耐药中的作用机制，为耐药干预提供新的靶点。

Oxaliplatin resistance is a significant cause of treatment failure and poor prognosis of colorectal cancer. Abnormal fatty acid anabolism is found to be associated with chemo-resistance. Our preliminary study indicated that ERCC2 and SREBP1 might form a function complex, which promotes fatty acid synthesis by regulating FASN, a key enzyme for fatty acid synthesis, and may be a new significant mechanism of oxaliplatin resistance in colorectal cancer. To further validate the above scientific hypothesis and clarify its detailed mechanism, we plan to perform immunofluorescence, co-immunoprecipitation and GST-pull-down experiments to confirm the combination of ERCC2 and SREBP1. CHIP/RE-CHIP and luciferase reporter assays will then be used to verify the ERCC2/SREBP1 compound can enrich in the region of FASN promoter and activate FASN expression. Lastly, we will confirm the impact of ERCC2/SREBP1-FASN pathway on fatty acid synthesis and oxaliplatin resistance of colorectal cancer by gene intervention experiments and human colorectal cancer tissues study. This project proposes for the first time the pivotal function of fatty acid anabolism for oxaliplatin resistance in colorectal cancer and explores the mechanism of ERCC2/SREBP1-FASN pathway in regulating fatty acid synthesis and oxaliplatin resistance, furnishing a novel potential target for the intervention of drug resistance.