Abstract：
: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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Wang YP,Zhou W,Wang J,Huang X,Zuo Y,Wang TS,Gao X,Xu YY,Zou SW,Liu YB,Cheng JK,Lei QYdoi
10.1016/j.molcel.2016.09.028subject
Has Abstractpub_date
2016-11-17 00:00:00pages
673-687issue
4eissn
1097-2765issn
1097-4164pii
S1097-2765(16)30577-9journal_volume
64pub_type
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