title: Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.
abstract: The identification of succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) mutations in human cancers has rekindled the idea that altered cellular metabolism can transform cells. Inactivating SDH and FH mutations cause the accumulation of succinate and fumarate, respectively, which can inhibit 2-oxoglutarate (2-OG)-dependent enzymes, including the EGLN prolyl 4-hydroxylases that mark the hypoxia inducible factor (HIF) transcription factor for polyubiquitylation and proteasomal degradation. Inappropriate HIF activation is suspected of contributing to the pathogenesis of SDH-defective and FH-defective tumours but can suppress tumour growth in some other contexts. IDH1 and IDH2, which catalyse the interconversion of isocitrate and 2-OG, are frequently mutated in human brain tumours and leukaemias. The resulting mutants have the neomorphic ability to convert 2-OG to the (R)-enantiomer of 2-hydroxyglutarate ((R)-2HG). Here we show that (R)-2HG, but not (S)-2HG, stimulates EGLN activity, leading to diminished HIF levels, which enhances the proliferation and soft agar growth of human astrocytes. These findings define an enantiomer-specific mechanism by which the (R)-2HG that accumulates in IDH mutant brain tumours promotes transformation and provide a justification for exploring EGLN inhibition as a potential treatment strategy.
authors.affiliation: Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Lee
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Duncan
authors.forename: Giselle
authors.initials: G
authors.lastname: Lopez
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.forename: Shakti
authors.initials: S
authors.lastname: Ramkissoon
authors.forename: Julie A
authors.initials: JA
authors.lastname: Losman
authors.forename: Päivi
authors.initials: P
authors.lastname: Joensuu
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bergmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.forename: Jeremy
authors.initials: J
authors.lastname: Travins
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.forename: Ryan
authors.initials: R
authors.lastname: Looper
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005977:Glutarates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D005977:Glutarates; D051793:Hypoxia-Inducible Factor 1; D009687:Nuclear Proteins; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; C447780:EGLN2 protein, human; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases