EZH2调控FBP1介导代谢重编程在结肠癌化疗抵抗的作用及机制研究

Drug surviving cells might contribute to a significant portion of relapses, metastasis and resistance after chemotherapy. Our previous studies shown that in drug surviving cells , the expression of EZH2 was highly increased and the glycolysis was enhanced and moreover, the FBP1 (Fructose-1,6-bisphosphatase) gene, which is the rate-limiting enzyme in gluconeogenesis was decreased significantly. Furtherly, the cells chemosensitivity increased and the FBP1 expression was up regulated after EZH2 interference. It suggested that EZH2 gene was associated with chemotherapy resistance of colon cancer, but the mechanism remay unclear. In this study, colon cancer cell models with corresponding gene (EZH2 and FBP1) silence or over-expression were constructed to observe the effect of EZH2 on glycolysis and metabolism reprogramming and chemotheresistance of colorectal cancer cells in vitro and in vivo. The regulation mechanism of EZH2 on FBP1 , and how FBP1 effect the production of ROS (reactive oxygen species) and the downstream signaling pathways were investegaed to elucidate the mechansim of chemoresistance. The study would interpret the regulation of EZH2 on FBP1 mediated metabolism reprogramming and their critical roles on colon cancer chemoresistance and would help to imply new target of colon cancer therapy.

肿瘤治疗后的残存细胞是肿瘤复发、转移、治疗抵抗的根源。本项目前期研究发现化疗后残存肿瘤细胞中具有甲基转移酶活性的基因EZH2表达增强，糖酵解增强，而糖异生关键基因果糖1,6磷酸酶(FBP1)表达减弱；进一步干扰EZH2后发现残存细胞的化疗敏感性增加，FBP1表达上调。提示EZH2与结肠癌化疗抵抗相关，但其机制不清。本研究拟建立EZH2 和FBP1高或低表达细胞及动物模型，通过体内、体外实验研究EZH2对代谢重编程的影响及其与结肠癌化疗抵抗的关系，阐明EZH2如何通过调控FBP1表达下调/缺失介导的肿瘤代谢重编程，继而进一步探讨FBP1如何通过调控ROS水平变化而影响下游信号通路，最终诱导肿瘤化疗抵抗的分子机制。本项目将从一个全新的角度阐明EZH2通过调控FBP1介导肿瘤能量代谢重编程并进一步促进结肠癌产生化疗抵抗的分子机制，为逆转结直肠癌化疗耐药、增加化疗敏感性提供新的思路和潜在靶点。

肿瘤治疗后的残存细胞是肿瘤复发、转移、治疗抵抗的根源, 其发生机制尚未完全阐明。本项目采用EZH2高低表达结肠癌细胞模型和转基因杂交小鼠模型,深入研究EZH2调控果糖1,6磷酸酶FBP1，进而促进结肠癌化疗抵抗的作用及分子机制。本课题组证实组蛋白甲基转移酶EZH2显著促进结肠癌增殖转移, EZH2表达与结肠癌有氧糖酵解、化疗抵抗表型呈显著正相关，且EHZ2与糖代谢关键分子FBP1存在蛋白间相互作用，是导致糖酵解增强、化疗抵抗的关键因素。阐明了EZH2抑制FBP1活性导致糖酵解增强，通过调控ROS水平变化而影响Wnt/β-catenin/TCF4 信号通路，最终诱导肿瘤化疗抵抗的分子机制。为逆转结直肠癌化疗耐药、增加化疗敏感性提供新的思路和潜在靶点。