title: D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.
abstract: Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α-KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Lin
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Saman
authors.initials: S
authors.lastname: Abbas
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Manoela
authors.initials: M
authors.lastname: Ortega
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Hakim
authors.initials: H
authors.lastname: Bouamar
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Yissela
authors.initials: Y
authors.lastname: Escobedo
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Varadarajan
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sudderth
authors.affiliation: Division of Hematology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Schulz
authors.affiliation: Division of Hematology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Deutsch
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ulz
authors.affiliation: Division of Hematology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Neumeister
authors.affiliation: 1] Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA [2] Department of Pathology and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hinck
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.affiliation: Department of Pediatrics, Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas 75390, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Division of Hematology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
authors.affiliation: 1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA [3] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Patricia L M
authors.initials: PL
authors.lastname: Dahia
authors.affiliation: 1] Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [2] Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas 78229, USA [3] Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA [4] South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas 78229, USA.
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D049308:Dioxygenases / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008745:Methylation; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D000429:Alcohol Oxidoreductases; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C558760:D2HGDH protein, human; D049308:Dioxygenases