基于脂质组学探索LSD1抑制剂SP2509抗食管癌细胞增殖的分子机制  

Lipidomics-based exploration of the molecular mechanism of LSD1 inhibitors against esophageal cancer cells proliferation

作　　者：李妍 杜原鑫 张俊飞 杨彩红[1] 张雍偲[3] 范彦英[1] LI Yan;DU Yuan-Xin;ZHANG Jun-Fei;YANG Cai-Hong;ZHANG Yong-Cai;FAN Yan-Ying(Department of Pharmacology,School of Basic Medicine,Shanxi Medical University,Yuci 030600,China;Affiliated Cancer Hospital of Shanxi Medical University,Taiyuan 030013,China;First Hospital of Shanxi Medical University,Taiyuan 030001,China)

机构地区：[1]山西医科大学基础医学院药理教研室,山西榆次030600 [2]山西医科大学附属肿瘤医院,山西太原030013 [3]山西医科大学第一医院,山西太原030001

出　　处：《海南医科大学学报》2025年第5期331-342,350,共13页Journal of Hainan Medical University

基　　金：国家自然科学基金资助项目(82304560);山西省自然科学基金资助项目(20210302124008)。

摘　　要：目的:脂质代谢失调是肿瘤最显著的代谢特征之一。目前食管癌(esophageal cancers,ESCA)细胞脂质代谢的上游调控机制尚不清楚。研究表明表观遗传修饰异常是导致肿瘤脂质代谢失调的重要因素。赖氨酸特异性组蛋白去甲基化酶1(Lysine-specific demethylase 1,LSD1),主要催化组蛋白H3第4位和第9位赖氨酸的去甲基化,ESCA细胞中脂质代谢失调是否与LSD1有关尚无研究报道。方法:利用CCK8细胞增殖实验、siRNA干扰实验、Western Blot蛋白免疫印迹实验、脂质组学技术及TCGA数据库,探索LSD1促进ESCA细胞增殖、调控其脂质代谢的分子机制。结果:ESCA细胞中存在明显的脂质代谢失调,表现在多种甘油磷脂如磷脂酰胆碱、磷脂酰乙醇胺含量显著上调和相关代谢酶的异常表达;LSD1抑制剂或干扰LSD1表达均可有效抑制ESCA细胞增殖;LSD1与参与磷脂酰胆碱和磷脂酰乙醇胺的合成与分解代谢关键酶的表达具有显著的相关性,其抑制剂可降低细胞中的磷脂酰胆碱、磷脂酰乙醇胺的含量、抑制mTOR通路的激活、下调固醇调节元件结合蛋白(sterol regulatory element-binding factor 1,SREBF1)的表达。结论:LSD1是调控ESCA细胞甘油磷脂代谢的上游靶点,其机制可能与激活mTOR通路调控SREBF1的表达有关。本研究揭示了LSD1在肿瘤发生、发展中的新角色,为开发针对ESCA等恶性肿瘤的精准治疗策略提供了有力的理论依据和潜在的治疗靶点。Objective:Dysregulation of lipid metabolism is one of the most prominent metabolic characteristics of tumors.At present,the upstream regulatory mechanism of lipid metabolism in esophageal cancers(ESCA)remains unknown.Studies have shown that abnormal epigenetic modifications are most important factors leading to the dysregulation of lipid metabolism in tumors.Lysine-specific demethylase 1(LSD1),which mainly removes the methyl group from mono-and demethylated histone H3 at lysine 4 or lysine 9.However,it is still unclear whether LSD1 is related to lipid metabolism disorder in ESCA cells.Methods:We Used CCK8 cell proliferation assay,siRNA interference assay,Western blot assays,lipidomics technology and TCGA database to explore the mechanism by which LSD1 regulates the proliferation and lipid metabolism of ESCA cells.Results:There was obvious lipid metabolism disorder in ESCA cells,which was manifested as significant upregulation of glycerophospholipids such as phosphatidylcholine(PC)and phosphatidylethanolamine(PE)and abnormal expression of related metabolic enzymes.LSD1 inhibitor or LSD1 knockdown inhibited the proliferation of ESCA cells.LSD1 had a significant correlation with the expression of key enzymes which were involved in the synthesis and catabolism of phosphatidylcholine and phosphatidylethanolamine.Further,SP2509 treatment reduced the contents of PC and PE in cells,which also inhibited the activation of mTOR signaling pathway and down-regulated the expression of sterol regulatory element-binding factor 1(SREBF1).Conclusion:LSD1 is an upstream target involving in the regulation of glycerophospholipids metabolism in ESCA cells,and its mechanism may be related to the activation of mTOR pathway and the regulation of SREBF1 expression.This study reveals a novel role of LSD1 in the occurrence and development of tumors,and also provides a strong theoretical basis and potential therapeutic target for the development of precision treatment strategies for malignant tumors such as ESCA.

关 键 词：脂质代谢失调 组蛋白赖氨酸去甲基化酶 食管癌 肿瘤细胞增殖 表观遗传修饰 

分 类 号：R735.1[医药卫生—肿瘤]