title: Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: wangyiping@shsmu.edu.cn.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Tian-Shi
authors.initials: TS
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Xu
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Shanghai Tenth People's Hospital, Tong Ji University, Shanghai 200072, China.
authors.forename: Shao-Wu
authors.initials: SW
authors.lastname: Zou
authors.affiliation: Department of General Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Ying-Bin
authors.initials: YB
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: jkcheng@shsmu.edu.cn.
authors.forename: Jin-Ke
authors.initials: JK
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Cancer Metabolism Laboratory, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: qlei@fudan.edu.cn.
authors.forename: Qun-Ying
authors.initials: QY
authors.lastname: Lei
mesh_terms: D001120:Arginine / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D050538:Malate Dehydrogenase (NADP+) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D009249:NADP / Q000096:biosynthesis; D010084:Oxidation-Reduction; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D005973:Glutamine; D009249:NADP; D001120:Arginine; D050538:Malate Dehydrogenase (NADP+); D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1
keywords: CARM1; KRAS; MDH1; arginine methylation; glutamine metabolism; mitochondrial respiration; nicotinamide adenine dinucleotide phosphate; pancreatic cancer; reactive oxygen species; redox homeostasis