Cell Reports (Sep 2018)

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

  • Xing-Yu Zhong,
  • Xiu-Ming Yuan,
  • Ying-Ying Xu,
  • Miao Yin,
  • Wei-Wei Yan,
  • Shao-Wu Zou,
  • Li-Ming Wei,
  • Hao-Jie Lu,
  • Yi-Ping Wang,
  • Qun-Ying Lei

Journal volume & issue
Vol. 24, no. 12
pp. 3207 – 3223

Abstract

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Summary: 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. : 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. Keywords: GAPDH, CARM1, arginine methylation, coenzyme affinity, glycolysis, AMPK, nutrient sensing, Warburg effect, metabolic reprogramming, liver cancer