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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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5-Methylcytosine / metabolism
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Amino Acid Substitution / physiology
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Animals
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Binding, Competitive
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Biocatalysis / drug effects
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Caenorhabditis elegans / enzymology
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / chemistry
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Caenorhabditis elegans Proteins / metabolism
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Catalytic Domain
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Cell Line, Tumor
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Cytosine / analogs & derivatives
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Cytosine / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dioxygenases / antagonists & inhibitors*
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Dioxygenases / metabolism
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Endostatins / metabolism
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F-Box Proteins
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Gene Expression / drug effects
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Gene Expression / genetics
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Glioma / enzymology*
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Glioma / genetics
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Glioma / metabolism
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Glutarates / chemistry
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Glutarates / metabolism
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Glutarates / pharmacology*
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Histone Demethylases / antagonists & inhibitors
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Histone Demethylases / metabolism
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Histones / metabolism
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Homeodomain Proteins / genetics
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Isocitrate Dehydrogenase / antagonists & inhibitors
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Isocitrate Dehydrogenase / genetics
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Isocitrate Dehydrogenase / metabolism
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
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Jumonji Domain-Containing Histone Demethylases / chemistry
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Jumonji Domain-Containing Histone Demethylases / metabolism
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Ketoglutaric Acids / chemistry
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Ketoglutaric Acids / metabolism*
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Ketoglutaric Acids / pharmacology
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Mixed Function Oxygenases
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Models, Molecular
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Oxalates / pharmacology
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Oxidoreductases, N-Demethylating / antagonists & inhibitors
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Oxidoreductases, N-Demethylating / metabolism
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Procollagen-Proline Dioxygenase / antagonists & inhibitors
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
Substances
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Caenorhabditis elegans Proteins
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DNA-Binding Proteins
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Endostatins
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F-Box Proteins
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Glutarates
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HIF1A protein, human
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Histones
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Homeodomain Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ketoglutaric Acids
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Oxalates
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Proto-Oncogene Proteins
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5-hydroxymethylcytosine
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HoxA protein
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alpha-hydroxyglutarate
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oxalomalic acid
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5-Methylcytosine
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Cytosine
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Mixed Function Oxygenases
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TET1 protein, human
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IDH2 protein, human
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Isocitrate Dehydrogenase
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IDH1 protein, human
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Dioxygenases
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TET2 protein, human
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Histone Demethylases
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JMJD-1.2 protein, C elegans
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Jumonji Domain-Containing Histone Demethylases
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EGLN1 protein, human
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Procollagen-Proline Dioxygenase
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KDM2A protein, human
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Hypoxia-Inducible Factor-Proline Dioxygenases
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Oxidoreductases, N-Demethylating