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      SIRT3-mediated dimerization of IDH2 directs cancer cell metabolism and tumor growth

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          Abstract

          The isocitrate dehydrogenase IDH2 produces α-ketoglutarate by oxidizing isocitrate, linking glucose metabolism to oxidative phosphorylation. In this study, we report that loss of SIRT3 increases acetylation of IDH2 at lysine 413 (IDH2-K413-Ac), thereby decreasing its enzymatic activity by reducing IDH2 dimer formation. Expressing a genetic acetylation mimetic IDH2 mutant (IDH2 K413Q) in cancer cells decreased IDH2 dimerization and enzymatic activity and increased cellular reactive oxygen species (ROS) and glycolysis, suggesting a shift in mitochondrial metabolism. Concurrently, overexpression of IDH2 K413Q promoted cell transformation and tumorigenesis in nude mice, resulting in a tumor-permissive phenotype. Immunohistochemical staining showed that IDH2 acetylation was elevated in high-risk luminal B patients relative to low-risk luminal A patients. Overall, these results suggest a potential relationship between SIRT3 enzymatic activity, IDH2-K413 acetylation-determined dimerization, and a cancer-permissive phenotype.

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          Author and article information

          Journal
          2984705R
          2786
          Cancer Res
          Cancer Res.
          Cancer research
          0008-5472
          1538-7445
          26 May 2017
          23 May 2017
          01 August 2017
          01 August 2018
          : 77
          : 15
          : 3990-3999
          Affiliations
          [1 ]Department of Radiation Oncology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
          [2 ]Driskill Graduate Program in Life Sciences, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
          [3 ]Department of Pharmacology, Robert Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
          [4 ]Department of General and Applied Toxicology, Innovative Toxicology Research Center, Korea Institute of Toxicology (KIT), Daejeon, 34114, Korea
          Author notes
          [# ]Corresponding Author: David Gius, M.D., Ph.D., Zell Family Scholar Professor, Director, Women’s Cancer Research Program, Robert H. Lurie Comprehensive Cancer Center, Vice Chairman Translation Research, Department of Radiation Oncology and Pharmacology, Northwestern University Feinberg School of Medicine, 303 East Superior, Rm 4-115, Chicago, IL 60611, 312-503-2053, david.gius@ 123456northwestern.edu
          [*]

          Indicates equal contribution

          Article
          PMC5540757 PMC5540757 5540757 nihpa878806
          10.1158/0008-5472.CAN-16-2393
          5540757
          28536275
          b8f76b8c-fa49-4ef7-b9c8-fb6c96da63dd
          History
          Categories
          Article

          Sirtuins,SIRT3,IDH2,Acetylation,Acetylome,Warburg effect,Glycolysis,Metabolism,Detoxification,Aging,Signaling

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