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
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
MeSH terms
- 5-Methylcytosine / metabolism
- Amino Acid Substitution / physiology
- Animals
- Binding, Competitive
- Biocatalysis / drug effects
- Caenorhabditis elegans / enzymology
- Caenorhabditis elegans Proteins / antagonists & inhibitors
- Caenorhabditis elegans Proteins / chemistry
- Caenorhabditis elegans Proteins / metabolism
- Catalytic Domain
- Cell Line, Tumor
- Cytosine / analogs & derivatives
- Cytosine / metabolism
- DNA-Binding Proteins / antagonists & inhibitors
- DNA-Binding Proteins / genetics
- DNA-Binding Proteins / metabolism
- Dioxygenases / antagonists & inhibitors*
- Dioxygenases / metabolism
- Endostatins / metabolism
- F-Box Proteins
- Gene Expression / drug effects
- Gene Expression / genetics
- Glioma / enzymology*
- Glioma / genetics
- Glioma / metabolism
- Glutarates / chemistry
- Glutarates / metabolism
- Glutarates / pharmacology*
- Histone Demethylases / antagonists & inhibitors
- Histone Demethylases / metabolism
- Histones / metabolism
- Homeodomain Proteins / genetics
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
- Hypoxia-Inducible Factor-Proline Dioxygenases
- Isocitrate Dehydrogenase / antagonists & inhibitors
- Isocitrate Dehydrogenase / genetics
- Isocitrate Dehydrogenase / metabolism
- Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
- Jumonji Domain-Containing Histone Demethylases / chemistry
- Jumonji Domain-Containing Histone Demethylases / metabolism
- Ketoglutaric Acids / chemistry
- Ketoglutaric Acids / metabolism*
- Ketoglutaric Acids / pharmacology
- Mixed Function Oxygenases
- Models, Molecular
- Oxalates / pharmacology
- Oxidoreductases, N-Demethylating / antagonists & inhibitors
- Oxidoreductases, N-Demethylating / metabolism
- Procollagen-Proline Dioxygenase / antagonists & inhibitors
- Procollagen-Proline Dioxygenase / genetics
- Procollagen-Proline Dioxygenase / metabolism
- Proto-Oncogene Proteins / antagonists & inhibitors
- Proto-Oncogene Proteins / genetics
- Proto-Oncogene Proteins / metabolism
Substances
- 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 protein, 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