S100P-SLC2A5-KHK驱动果糖代谢促结肠癌增殖及化疗抵抗的分子机制

表观遗传调控和能量代谢改变是介导肿瘤发生发展的重要因素，但DNA去甲基化协同果糖代谢调控结肠癌增殖及化疗抵抗的机制尚无报道。我们前期工作发现：1.结肠癌中S100P核异位能促进SLC2A5表达，SLC2A5高表达与病人的不良预后相关；2.在葡萄糖缺乏时，SLC2A5可通过调节果糖利用维持细胞生存；3.SLC2A5促进关键限速酶果糖激酶（KHK）蛋白的表达。由此提出假说：S100P-SLC2A5-KHK可能是调节“摄糖转换”驱动糖酵解维持肿瘤细胞生存的关键信号轴。在此基础上，本课题拟进一步揭示核S100P调控SLC2A5启动子去甲基化的表观遗传机制；阐明SLC2A5与KHK互作加速果糖驱动糖酵解的分子机制；探讨靶向抑制SLC2A5或低果糖饮食对肿瘤细胞化疗效果的影响。本研究旨在揭示DNA去甲基化调控 “摄能转换”促进果糖代谢介导结肠癌增殖的新机制，以期为结肠癌治疗提供新靶点和新思路。

Interaction of epigenetic regulation and energy metabolism are important factors in mediating tumorigenesis and development, but the mechanism of DNA demethylation and fructose metabolism synergistically regulating colon cancer proliferation and chemoresistance have not been reported. Our previous work found that: 1. S100P nuclear translocation could promote the expression of SLC2A5, and high expression of SLC2A5 was associated with poorer prognosis of patients with colon cancer. 2. In the absence of glucose, SLC2A5 could maintain cell survival by regulating fructose manipulation. 3. SLC2A5 could promote the protein expression of the key rate-limiting enzyme fructokinase (KHK). Therefore, we presume that S100P-SLC2A5-KHK may be the key signal axis in regulating fructose-mediated glycolysis to promote colon cancer survival. Our study will further clarify 1. the epigenetic mechanism of S100P enhances SLC2A5 transcriptional activity in the nucleus; 2. the molecular mechanism by which SLC2A5 regulates fructose-mediated glycolysis to maintain tumor cell survival; 3. and the effect of targeted inhibition of SLC2A5 or low fructose diet on chemotherapy efficacy of tumor cells. This study aims to unveil a novel mechanism of fructose-mediated glycolysis in promoting colon cancer and provide a potentially selective target and therapy strategy for adjuvant therapy.