化疗药物抵抗是制约结直肠癌患者治疗效果和生存预后的关键瓶颈，但其分子机制尚未完全阐明。申请人前期研究发现LIMK1促进结直肠癌化疗抵抗，并初步证实HIF-1α上调LIMK1表达并抑制m6A识别蛋白YTHDC2表达，而YTHDC2与LIMK1 mRNA存在相互作用。据此提出假设：在结直肠癌中，缺氧条件下HIF-1α表达上调并转录抑制YTHDC2的表达，后者与LIMK1 mRNA结合并通过m6A甲基化增强 LIMK1 mRNA稳定性与翻译效率，促进LIMK1蛋白的表达从而介导化疗抵抗。本项目从表观遗传的角度，阐明YTHDC2调控LIMK1 m6A甲基化在HIF-1α促进结直肠癌化疗抵抗中的作用，为克服结直肠癌化疗抵抗提供实验数据及新思路。

Chemotherapy resistance is a key bottleneck in restricting the treatment effect and survival prognosis of colorectal cancer patients, but its molecular mechanism has not been fully elucidated.Our previous study found that LIMK1 promoted colorectal cancer chemotherapy resistance, and we confirmed that HIF-1α promotes LIMK1, inhibits the expression of m6A reader protein YTHDC2, and YTHDC2 interacts with LIMK1 mRNA. Thus we suppose that in colorectal cancer, HIF-1α is up-regulated under hypoxic conditions and transcriptionally inhibits the expression of YTHDC2 , which binds to LIMK1 mRNA and enhances the stability and translation efficiency of LIMK1 mRNA through m6A methylation, and the over-expressed LIMK1 mediates chemotherapy resistance. This project clarifies the role of YTHDC2 in regulating LIMK1 m6A methylation in HIF-1α-mediated colorectal cancer chemotherapy resistance from an epigenetic perspective, and provides experimental data and new ideas for overcoming colorectal cancer chemotherapy resistance.