CARM1 Methylates GAPDH to Regulate Glucose Metabolism and Is Suppressed in Liver Cancer

• Published in: Cell reports (Cambridge) Vol. 24; no. 12; pp. 3207 - 3223
• Main Authors: Zhong, Xing-Yu, Yuan, Xiu-Ming, Xu, Ying-Ying, Yin, Miao, Yan, Wei-Wei, Zou, Shao-Wu, Wei, Li-Ming, Lu, Hao-Jie, Wang, Yi-Ping, Lei, Qun-Ying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.09.2018; Elsevier
• Subjects: AMPK; Animals; arginine methylation; Carcinoma, Hepatocellular - metabolism; CARM1; Cells, Cultured; coenzyme affinity; GAPDH; Glucose - metabolism; Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; Glycolysis; HEK293 Cells; Hep G2 Cells; Humans; liver cancer; Liver Neoplasms - metabolism; Male; metabolic reprogramming; Mice; Mice, Inbred BALB C; Mice, Nude; nutrient sensing; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Warburg effect; arginine methylation; CARM1; glycolysis; nutrient sensing; coenzyme affinity; AMPK; liver cancer; GAPDH; metabolic reprogramming; Warburg effect
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.08.066

Increased aerobic glycolysis is a hallmark of cancer metabolism. How cancer cells coordinate glucose metabolism with extracellular glucose levels remains largely unknown. Here, we report that coactivator-associated arginine methyltransferase 1 (CARM1 or PRMT4) signals glucose availability to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and suppresses glycolysis in liver cancer cells. CARM1 methylates GAPDH at arginine 234 (R234), inhibiting its catalytic activity. Glucose starvation leads to CARM1 upregulation, further inducing R234 hypermethylation and GAPDH inhibition. The re-expression of wild-type GAPDH, but not of its methylation-mimetic mutant, sustains glycolytic levels. CARM1 inhibition increases glycolytic flux and glycolysis. R234 methylation delays tumor cell proliferation in vitro and in vivo. Compared with normal tissues, R234 is hypomethylated in malignant clinical hepatocellular carcinoma samples. Notably, R234 methylation positively correlates with CARM1 expression in these liver cancer samples. Our findings thus reveal that CARM1-mediated GAPDH methylation is a key regulatory mechanism of glucose metabolism in liver cancer. [Display omitted] •CARM1 methylates and inhibits GAPDH in an AMPK-dependent manner•GAPDH methylation represses glycolysis and proliferation of liver cancer cells•R234 methylation is positively correlated with CARM1 in hepatocellular carcinoma GAPDH is a critical enzyme in glycolysis. Zhong et al. find that CARM1 methylates GAPDH at R234 and inhibits its activity in an AMPK-dependent manner. R234 methylation inhibits glycolysis and proliferation of liver cancer cell lines. In hepatocellular carcinoma patient samples, GADPH R234 is hypomethylated, and there is a positive correlation between CARM1 levels and R234 methylation.