Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer
2016
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- Autor(en) / Beteiligte
- Titel
- Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer
- Ist Teil von
- Molecular cell, 2016-11, Vol.64 (4), p.673-687
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •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 Wang et al. show that arginine methylation at R248 of MDH1, which is catalyzed by PRMT4/CARM1, regulates glutamine metabolism and redox homeostasis of pancreatic cancer cells. MDH1 methylation is downregulated in human PDAC samples.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/j.molcel.2016.09.028Titel-ID: cdi_proquest_miscellaneous_1839112449
- Format
- –
- Schlagworte
- Arginine - metabolism, arginine methylation, Carcinoma, Pancreatic Ductal - genetics, Carcinoma, Pancreatic Ductal - metabolism, Carcinoma, Pancreatic Ductal - pathology, CARM1, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glutamine - metabolism, HEK293 Cells, Humans, KRAS, Malate Dehydrogenase (NADP+) - antagonists & inhibitors, Malate Dehydrogenase (NADP+) - genetics, Malate Dehydrogenase (NADP+) - metabolism, MDH1, Methylation, Mitochondria - genetics, Mitochondria - metabolism, Mitochondria - pathology, mitochondrial respiration, Models, Molecular, NADP - biosynthesis, nicotinamide adenine dinucleotide phosphate, Oxidation-Reduction, pancreatic cancer, Pancreatic Neoplasms - genetics, Pancreatic Neoplasms - metabolism, Pancreatic Neoplasms - pathology, Protein Multimerization, Protein Structure, Secondary, Protein-Arginine N-Methyltransferases - genetics, Protein-Arginine N-Methyltransferases - metabolism, reactive oxygen species, redox homeostasis, RNA, Small Interfering - genetics, RNA, Small Interfering - metabolism, Signal Transduction