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PMID: 21251613 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.

Cancer cell ·Vol. 19 ·No. 1 ·2011-01-18 ·Pages 17-30

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y

Abstract

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

MeSH Terms
5-Methylcytosine/metabolism Amino Acid Substitution/physiology Animals Binding, Competitive Biocatalysis/drug effects Caenorhabditis elegans/enzymology Caenorhabditis elegans Proteins/antagonists & inhibitors,chemistry,metabolism Catalytic Domain Cell Line, Tumor Cytosine/analogs & derivatives,metabolism DNA-Binding Proteins/antagonists & inhibitors,genetics,metabolism Dioxygenases/antagonists & inhibitors,metabolism Endostatins/metabolism F-Box Proteins Gene Expression/drug effects,genetics Glioma/enzymology,genetics,metabolism Glutarates/chemistry,metabolism,pharmacology Histone Demethylases/antagonists & inhibitors,metabolism Histones/metabolism Homeodomain Proteins/genetics Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Hypoxia-Inducible Factor-Proline Dioxygenases Isocitrate Dehydrogenase/antagonists & inhibitors,genetics,metabolism Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors,chemistry,metabolism Ketoglutaric Acids/chemistry,metabolism,pharmacology Mixed Function Oxygenases Models, Molecular Oxalates/pharmacology Oxidoreductases, N-Demethylating/antagonists & inhibitors,metabolism Procollagen-Proline Dioxygenase/antagonists & inhibitors,genetics,metabolism Proto-Oncogene Proteins/antagonists & inhibitors,genetics,metabolism
Chemicals
Caenorhabditis elegans Proteins DNA-Binding Proteins Endostatins F-Box Proteins Glutarates HIF1A protein, human Histones Homeodomain Proteins Hypoxia-Inducible Factor 1, alpha Subunit Ketoglutaric Acids Oxalates Proto-Oncogene Proteins 5-hydroxymethylcytosine HoxA protein alpha-hydroxyglutarate oxalomalic acid 5-Methylcytosine Cytosine Mixed Function Oxygenases TET1 protein, human IDH2, human Isocitrate Dehydrogenase IDH1 protein, human Dioxygenases TET2 protein, human Histone Demethylases JMJD-1.2 protein, C elegans Jumonji Domain-Containing Histone Demethylases EGLN1 protein, human Procollagen-Proline Dioxygenase KDM2A protein, human Hypoxia-Inducible Factor-Proline Dioxygenases Oxidoreductases, N-Demethylating
Authors & Affiliations
22 authors, click to expand affiliations / ORCID
Xu Wei
State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai Medical School, Fudan University, Shanghai 20032, China.
Yang Hui
Liu Ying
Yang Ying
Wang Ping
Kim Se-Hee
Ito Shinsuke
Yang Chen
Wang Pu
Xiao Meng-Tao
Liu Li-xia
Jiang Wen-qing
Liu Jing
Zhang Jin-ye
Wang Bin
Frye Stephen
Zhang Yi
Xu Yan-hui
Lei Qun-ying
Guan Kun-Liang
Zhao Shi-min
Xiong Yue
References (51)
51 references, click to expand
  1. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
    Cell. 1997 Jan 24;88(2):277-85 PMID: 9008168
  2. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer.
    J Biol Chem. 1999 May 28;274(22):15633-45 PMID: 10336460
  3. Hydroxyglutaric aciduria and malignant brain tumor: a case report and literature review.
    J Neurooncol. 2009 Jan;91(2):233-6 PMID: 18931888
  4. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification.
    Nature. 2010 Aug 26;466(7310):1129-33 PMID: 20639862
  5. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
    Science. 2001 Apr 20;292(5516):464-8 PMID: 11292862
  6. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.
    Science. 2009 May 15;324(5929):930-5 PMID: 19372391
  7. H3K79 methylation profiles define murine and human MLL-AF4 leukemias.
    Cancer Cell. 2008 Nov 4;14(5):355-68 PMID: 18977325
  8. A conserved family of prolyl-4-hydroxylases that modify HIF.
    Science. 2001 Nov 9;294(5545):1337-40 PMID: 11598268
  9. Recurring mutations found by sequencing an acute myeloid leukemia genome.
    N Engl J Med. 2009 Sep 10;361(11):1058-66 PMID: 19657110
  10. Expanding chemical biology of 2-oxoglutarate oxygenases.
    Nat Chem Biol. 2008 Mar;4(3):152-6 PMID: 18277970
  11. IDH1 and IDH2 mutations in gliomas.
    N Engl J Med. 2009 Feb 19;360(8):765-73 PMID: 19228619
  12. Mutation in TET2 in myeloid cancers.
    N Engl J Med. 2009 May 28;360(22):2289-301 PMID: 19474426
  13. The importance of proline residues in the structure, stability and susceptibility to proteolytic degradation of collagens.
    Amino Acids. 2008 Nov;35(4):703-10 PMID: 18431533
  14. Histone demethylation by a family of JmjC domain-containing proteins.
    Nature. 2006 Feb 16;439(7078):811-6 PMID: 16362057
  15. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.
    Science. 2000 Feb 4;287(5454):848-51 PMID: 10657297
  16. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain.
    Science. 2009 May 15;324(5929):929-30 PMID: 19372393
  17. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations.
    J Exp Med. 2010 Feb 15;207(2):339-44 PMID: 20142433
  18. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
    Cancer Cell. 2005 Jan;7(1):77-85 PMID: 15652751
  19. Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids.
    Cell Cycle. 2009 Jun 1;8(11):1698-710 PMID: 19411852
  20. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.
    Genes Dev. 2001 Oct 15;15(20):2675-86 PMID: 11641274
  21. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma.
    Hum Mol Genet. 2007 Dec 15;16(24):3136-48 PMID: 17884808
  22. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.
    Cancer Cell. 2010 Jan 19;17(1):98-110 PMID: 20129251
  23. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma.
    Cancer Cell. 2010 May 18;17(5):510-22 PMID: 20399149
  24. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
    Cancer Cell. 2010 Mar 16;17(3):225-34 PMID: 20171147
  25. L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.
    Hum Mol Genet. 2004 Nov 15;13(22):2803-11 PMID: 15385440
  26. An integrated genomic analysis of human glioblastoma multiforme.
    Science. 2008 Sep 26;321(5897):1807-12 PMID: 18772396
  27. Fe(II)/alpha-ketoglutarate hydroxylases involved in nucleobase, nucleoside, nucleotide, and chromatin metabolism.
    Dalton Trans. 2008 Oct 14;(38):5132-42 PMID: 18813363
  28. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
    Nature. 2009 Dec 10;462(7274):739-44 PMID: 19935646
  29. Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H.
    Cell Res. 2010 Nov;20(11):1188-200 PMID: 20975740
  30. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
    Cell. 2001 Oct 5;107(1):43-54 PMID: 11595184
  31. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas.
    Am J Pathol. 2009 Apr;174(4):1149-53 PMID: 19246647
  32. JARID1B is a histone H3 lysine 4 demethylase up-regulated in prostate cancer.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19226-31 PMID: 18048344
  33. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23).
    Leukemia. 2003 Mar;17(3):637-41 PMID: 12646957
  34. Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins.
    J Inorg Biochem. 2006 Apr;100(4):644-69 PMID: 16513174
  35. Structural insights into histone demethylation by JMJD2 family members.
    Cell. 2006 May 19;125(4):691-702 PMID: 16677698
  36. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation.
    Cancer Cell. 2010 Dec 14;18(6):553-67 PMID: 21130701
  37. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor.
    Genes Dev. 2002 Jun 15;16(12):1466-71 PMID: 12080085
  38. Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase.
    Nat Struct Mol Biol. 2007 Aug;14(8):689-95 PMID: 17589523
  39. The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
    Cell Metab. 2010 May 5;11(5):364-78 PMID: 20399150
  40. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria.
    Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16849-54 PMID: 15548604
  41. Quantification of the sixth DNA base hydroxymethylcytosine in the brain.
    Angew Chem Int Ed Engl. 2010 Jul 19;49(31):5375-7 PMID: 20583021
  42. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.
    Cancer Cell. 2005 Aug;8(2):143-53 PMID: 16098467
  43. PLU-1 is an H3K4 demethylase involved in transcriptional repression and breast cancer cell proliferation.
    Mol Cell. 2007 Mar 23;25(6):801-12 PMID: 17363312
  44. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
    Science. 2001 Apr 20;292(5516):468-72 PMID: 11292861
  45. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha.
    Science. 2009 Apr 10;324(5924):261-5 PMID: 19359588
  46. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
    Nat Genet. 2002 Apr;30(4):406-10 PMID: 11865300
  47. Acquired mutations in TET2 are common in myelodysplastic syndromes.
    Nat Genet. 2009 Jul;41(7):838-42 PMID: 19483684
  48. Novel inhibitors of prolyl 4-hydroxylase. 3. Inhibition by the substrate analogue N-oxaloglycine and its derivatives.
    J Med Chem. 1992 Jul 10;35(14):2652-8 PMID: 1321909
  49. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.
    Hum Mol Genet. 2005 Aug 1;14(15):2231-9 PMID: 15987702
  50. Diagnostic and prognostic markers in gliomas.
    Curr Opin Oncol. 2009 Nov;21(6):537-42 PMID: 19667985
  51. LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23).
    Cancer Res. 2002 Jul 15;62(14):4075-80 PMID: 12124344
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2010.12.014
Published
2011-01-18
Pages
17-30
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3229304
Subset
IM
Grants
NCI NIH HHS · R01 CA068377 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · R01 CA068377-13 · United States
NCI NIH HHS · R01 CA068377-14 · United States
NCI NIH HHS · R01 CA068377-12 · United States
Databases
PDB
3PUQ, 3PUR
External Links
PubMed source DOI: 10.1016/j.ccr.2010.12.014 PMC Full Text View journal details
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