title: Hypoxia Induces Production of L-2-Hydroxyglutarate.
abstract: Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the "oncometabolite" D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3).
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Dematteo
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ariën S
authors.initials: AS
authors.lastname: Rustenburg
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Grinaway
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Chodera
authors.affiliation: The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: thompsonc@mskcc.org.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005977:Glutarates / Q000378:metabolism*; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008745:Methylation; D051379:Mice
chemical_list: D005977:Glutarates; D006657:Histones; D007527:Isoenzymes; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse; C543588:IDH1 protein, human