LSD1调控Sp1/DPD促进5-FU代谢失活诱导5-FU胃癌耐药的机制研究

5-FU是临床一线广谱抗肿瘤药，但其耐药性严重影响疗效。二氢嘧啶脱氢酶（DPD）是5-FU代谢失活的关键限速酶，其在肿瘤中表达和活性的改变能够显著影响5-FU敏感性，然而DPD表达的调控机制尚未完全清楚。组蛋白赖氨酸特异性去甲基化酶1（LSD1）在多种肿瘤中高表达与化疗药物的疗效密切相关。我们前期研究首次发现，抑制LSD1能够显著降低DPD表达、抑制Sp1转录活性，并增加胃癌细胞内5-FU含量、降低其代谢产物水平，有效逆转胃癌5-FU耐药，提示LSD1可能通过调控Sp1/DPD通路影响5-FU敏感性。本项目将利用基因编辑及ChIP等生物学手段深入阐明LSD1如何调控肿瘤组织DPD表达，促进5-FU代谢失活诱导5-FU耐药的新机制，评估LSD1抑制剂与5-FU联用的抗胃癌疗效。项目预期结果将为LSD1抑制剂作为5-FU耐药逆转剂的研发奠定理论基础，同时为临床5-FU耐药胃癌的治疗提供新思路。

5-FU is a first-line broad-spectrum anticancer drug in clinic, but the resistance of 5-FU seriously affects its clinical efficacy. Dihydropyrimidine dehydrogenase (DPD) is a key rate-limiting enzyme in the inactivation of 5-FU metabolism, and its expression and activity changes in tumor tissues could significantly affect the sensitivity of 5-FU. However, the regulatory mechanism of DPD expression is not entirely clear. It was reported that high expression of histone lysine specific demethylase 1 (LSD1) in most tumor tissues was closely related to the efficacy of chemotherapy drugs. Our previous study firstly showed that inhibition of LSD1 could significantly reduce DPD expression, inhibit the transcriptional activity of Sp1, increase the intracellular 5-FU content, decrease the level of 5-FU metabolites and effectively reverse the 5-FU resistance in gastric cancer, suggesting that LSD1 regulates the sensitivity of 5-FU by Sp1/DPD pathway. Based on the biology methods including gene editing and ChIP assays, this project would further elucidate the new mechanism of LSD1 regulating DPD expression in tumor tissues and inducing 5-FU metabolic inactivation and resistance, and evaluate the anti-tumor efficacy of LSD1 inhibitors combined with 5-FU. The expected results of this project will not only lay a theoretical foundation for the research and development of LSD1 inhibitors as a 5-FU resistance reversal agent, but also provide new ideas for the clinical treatment of 5-FU resistance gastric cancer.