Arginine Methylation of MDH1 Disrupts PDAC Metabolism and Growth

In pancreatic ductal adenocarcinoma (PDAC), KRAS activation drives a unique metabolic dependency on glutamine. In a noncanonical glutamine metabolic pathway, glutamine-derived aspartate is converted to pyruvate in a series of reactions catalyzed by GOT1, malate dehydrogenase 1 (MDH1), and malic enzyme 1 (ME1) that result in NADPH production. Post-translational arginine methylation of MDH1 has been observed in mice, but the role of MDH1 methylation in PDAC glutamine metabolism is unclear. Wang and colleagues found that the protein arginine methyltransferase CARM1 (also known as PRMT4) methylated MDH1 at R248, blocking MDH1 dimerization and thereby reducing its catalytic activity. MDH1 is a component of the malate–aspartate shuttle that normally carries reducing equivalents from glycolysis across the mitochondrial membrane for mitochondrial respiration, and MDH1 methylation inhibited malate–aspartate shuttling and mitochondrial respiration. MDH1 also catalyzes the reversible conversion between malate and oxaloacetate in glutamine metabolism and is required for glutamine-dependent NADPH production, and depletion of CARM1 increased malate levels and the NADPH/NADP⁺ ratio and reduced levels of aspartate and reactive oxygen species, suggesting that arginine methylation of MDH1 disrupts glutamine metabolism and redox balance. Activation of KRAS, one of the most common genetic events in PDAC, reduced CARM1-mediated MDH1 arginine methylation, enhancing MDH1 activity. In PDAC cells, MDH1 prevented cell death in response to oxidative damage, further supporting a role for MDH1 in redox homeostasis and PDAC cell survival. CARM1-mediated MDH1 methylation reduced proliferation and colony formation in PDAC cells, whereas CARM1 depletion enhanced proliferation. MDH1 was found to be hypomethylated in 20 PDAC samples compared with paired adjacent tissue, and MDH1 hypomethylation was associated with reduced expression of CARM1, suggesting loss of CARM1-mediated MDH1 arginine methylation provides a selective advantage in PDAC. Moreover, the finding that MDH1 arginine methylation regulates glutamine metabolism and redox homeostasis to suppress PDAC proliferation suggests the potential for the development of CARM1 activators to suppress PDAC.

Wang YP, Zhou W, Wang J, Huang X, Zuo Y, Wang TS, et al. Arginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer. Mol Cell 2016 Nov 10 [Epub ahead of print].