title: D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth.
abstract: Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, SJTU-SM, Shanghai 200025, China.
authors.forename: Wanglong
authors.initials: W
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhong-Kai
authors.initials: ZK
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Fei-Zhen
authors.initials: FZ
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005977:Glutarates / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007656:Ketoglutaric Acids / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
chemical_list: D005977:Glutarates; D007656:Ketoglutaric Acids; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C019417:alpha-hydroxyglutarate; D006899:Mixed Function Oxygenases; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: D-2-HG; D2HGDH; IDH mutation; tumorigenesis
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