Molecular Cell
Volume 64, Issue 4, 17 November 2016, Pages 673-687
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Article
Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer

https://doi.org/10.1016/j.molcel.2016.09.028Get rights and content
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Highlights

  • Arginine methylation at R248 negatively regulates MDH1 activity

  • PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization

  • MDH1 methylation suppresses glutamine metabolism of pancreatic cancer

  • R248 methylation of MDH1 is downregulated in clinical PDAC samples

Summary

Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.

Keywords

CARM1
MDH1
arginine methylation
pancreatic cancer
glutamine metabolism
KRAS
redox homeostasis
nicotinamide adenine dinucleotide phosphate
reactive oxygen species
mitochondrial respiration

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