Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer  

作　　者：Yu-fei Wang Li-na Zhao Yu Geng Hong-feng Yuan Chun-yu Hou Hui-hui Zhang Guang Yang Xiao-dong Zhang 

机构地区：[1]Department of Cancer Research,College of Life Sciences,Nankai University,Weijin Road 94,Tianjin,300071,China [2]Department of Gastrointestinal Cancer Biology,Tianjin Cancer Institute,Liver Cancer Center,Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Huanhu Xi Road,Tiyuan Bei,Hexi District,Tianjin,300060,China

出　　处：《Acta Pharmacologica Sinica》2023年第1期211-220,共10页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(No.82103066).

摘　　要：Aspirin as a chemopreventive agent is able to restrict the tumor growth.Phosphoglycerate mutase 1(PGAM1)is a key enzyme of glycolysis,playing an important role in the development of cancer.However,the underlying mechanism by which aspirin inhibits the proliferation of cancer cells is poorly understood.This study aims to identify the effects of aspirin on modulating PGAM1 enzymatic activities in liver cancer.Here,we found that aspirin attenuated the PGAM1 succinylation to suppress the PGAM1 enzymatic activities and glycolysis in hepatoma cells.Mechanically,aspirin remarkably reduced the global succinylation levels of hepatoma cells,including the PGAM1 succinylation,which led to the block of conversion from 3-phosphoglycerate(3-PG)to 2-phosphoglycerate(2-PG)in cells.Interestingly,RNA-seq analysis identified that aspirin could significantly decrease the levels of histone acetyltransferase 1(HAT1),a writer of PGAM1 succinylation,in liver cancer.As a target of aspirin,NF-κB p65 could effectively up-regulate the expression of HAT1 in the system,resulting in the increase of PGAM1 enzymatic activities.Moreover,we observed that the PGAM1-K99R mutant failed to rescue the aspirin-induced inhibition of PGAM1 activities,glycolysis,and proliferation of hepatoma cells relative to PGAM1-WT.Functionally,aspirin down-regulated HAT1 and decreased the PGAM1 succinylation levels in the tumor tissues from mice treated with aspirin in vivo.Thus,we conclude that aspirin modulates PGAM1K99 succinylation to restrict the PGAM1 activities and glycolysis through NF-κB p65/HAT1/PGAM1 signaling in liver cancer.Our finding provides new insights into the mechanism by which aspirin inhibits glycolysis in hepatocellular carcinoma.

关 键 词：ASPIRIN HAT1 PGAM1 SUCCINYLATION GLYCOLYSIS hepatoma carcinoma 

分 类 号：R73[医药卫生—肿瘤]