葡萄糖饥饿条件下AMPK-HDAC4-HSP90β1信号通路促进结肠癌细胞增殖的分子机制研究

由于肿瘤细胞快速增殖的特性，导致实体瘤细胞多处于低糖微环境中，但肿瘤细胞如何适应低糖应激进而发生发展的机制尚未完全明确。研究表明HSP90β1是热休克蛋白90 (HSP90)家族重要的成员之一，属于内质网应激蛋白，与肿瘤的发生发展密切相关。我们前期的研究表明：在葡萄糖饥饿条件下，结肠癌细胞中组蛋白去乙酰化酶HDAC4介导了活化的AMPK促进HSP90β1的表达。此外，在结肠癌细胞中下调HSP90β1的表达，能抑制糖酵解关键酶HK2的表达和细胞的增殖。由此我们推测：葡萄糖缺乏时，激活的AMPK通过调控HDAC4促进HSP90β1表达，进而调节肿瘤细胞糖酵解通路，最终促进了肿瘤细胞在低糖环境下的生长。本项目拟进一步采用慢病毒包装，免疫共沉淀，ChIP等技术方法，阐明AMPK-HDAC4-HSP90β1通路在结肠癌发生发展中的作用及调控机制，为确立HSP90β1作为抗肿瘤治疗的靶点提供理论依据。

Since the rapid proliferation of tumor cells, many solid tumor cells are exposed to low-glucose microenvironment. However, the mechanism of tumor cells development under low-glucose stress has not been fully understood. Studies have shown that HSP90β1 is an important endoplasmic reticulum stress protein of heat shock proteins 90 family, which is closely related to the occurrence and development of tumors. Our previous studies have shown that histone deacetylase HDAC4 mediates AMPK promoting HSP90β1expression in colon cancer cells under glucose starvation, and the expression of HSP90β1 was down-regulated, which could inhibit the proliferation of colon cancer cells, and the expression of HK2, a key glycolytic enzyme, was also decreased. Therefore, we hypothesized that the activated AMPK could regulate the expression of HSP90β1by regulating HDAC4, then regulate the glycolytic pathway of tumor cells, and finally promote the growth of tumor cells in low glucose environment. The aim of this project is to further explore the role of AMPK/HDAC4/HSP90β1pathway in the development and progression of Colon cancer and its specific regulatory mechanism by using lentivirus packaging, co-immunoprecipitation, ChIP and other techniques, to provide a theoretical basis for HSP90β1 as a clinical target in the treatment of colon cancer.