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

Yu-fei Wang1, Li-na Zhao1, Yu Geng1, Hong-feng Yuan2, Chun-yu Hou2, Hui-hui Zhang2, Guang Yang2, Xiao-dong Zhang1,2
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
Correspondence to: Guang Yang:, Xiao-dong Zhang:,
DOI: 10.1038/s41401-022-00945-z
Received: 22 March 2022
Accepted: 16 June 2022
Advance online: 14 July 2022


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.
Keywords: aspirin; HAT1; PGAM1; succinylation; glycolysis; hepatoma carcinoma

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