Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 131 Dong'an Road, Shanghai 200032, China.
Cancer Institute, Fudan University Shanghai Cancer Center and Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai 200032, China; Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 131 Dong'an Road, Shanghai 200032, China.
Cell Rep. 2018 Sep 18;24(12):3207-3223. 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.
糖酵解增加是癌症代谢的一个标志。癌细胞如何将葡萄糖代谢与细胞外葡萄糖水平相协调在很大程度上尚不清楚。在这里，我们报告共激活因子相关精氨酸甲基转移酶 1（CARM1 或 PRMT4）将葡萄糖可用性信号传递给甘油醛-3-磷酸脱氢酶（GAPDH），并抑制肝癌细胞中的糖酵解。CARM1 在精氨酸 234（R234）处使 GAPDH 甲基化，抑制其催化活性。葡萄糖饥饿导致 CARM1 上调，进一步诱导 R234 过度甲基化和 GAPDH 抑制。野生型 GAPDH 的重新表达，但不是其甲基化模拟突变体的表达，维持了糖酵解水平。CARM1 抑制增加了糖酵解通量和糖酵解。R234 甲基化在体外和体内延迟了肿瘤细胞的增殖。与正常组织相比，恶性临床肝细胞癌样本中的 R234 呈低甲基化。值得注意的是，R234 甲基化与这些肝癌样本中的 CARM1 表达呈正相关。因此，我们的发现揭示了 CARM1 介导的 GAPDH 甲基化是肝癌中葡萄糖代谢的关键调节机制。
