Document Detail

IDH mutation impairs histone demethylation and results in a block to cell differentiation.
MedLine Citation:
PMID:  22343901     Owner:  NLM     Status:  MEDLINE    
Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate. Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro. Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.
Chao Lu; Patrick S Ward; Gurpreet S Kapoor; Dan Rohle; Sevin Turcan; Omar Abdel-Wahab; Christopher R Edwards; Raya Khanin; Maria E Figueroa; Ari Melnick; Kathryn E Wellen; Donald M O'Rourke; Shelley L Berger; Timothy A Chan; Ross L Levine; Ingo K Mellinghoff; Craig B Thompson
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-02-15
Journal Detail:
Title:  Nature     Volume:  483     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-22     Completed Date:  2012-04-19     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  474-8     Citation Subset:  IM    
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
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MeSH Terms
3T3-L1 Cells
Adipocytes / cytology,  drug effects,  metabolism
Astrocytes / cytology,  drug effects
Cell Differentiation / drug effects,  genetics*
Cell Line, Tumor
Cell Lineage / genetics
DNA Methylation / drug effects
Enzyme Induction / drug effects
Gene Expression Regulation / drug effects
Glioma / enzymology,  genetics,  pathology
Glutarates / metabolism,  pharmacology
HEK293 Cells
Histones / metabolism*
Isocitrate Dehydrogenase / antagonists & inhibitors,  genetics*,  metabolism
Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors,  deficiency,  genetics,  metabolism
Methylation / drug effects
Mutation / genetics*
Neural Stem Cells / metabolism
Promoter Regions, Genetic / genetics
Grant Support
R01 CA078831/CA/NCI NIH HHS; R01 CA105463/CA/NCI NIH HHS; U54CA143798/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Glutarates; 0/Histones; 0/KDM4C protein, human; 2889-31-8/alpha-hydroxyglutarate; EC Dehydrogenase; EC 1.14.11.-/Jumonji Domain-Containing Histone Demethylases
Comment In:
Nat Rev Cancer. 2012 Apr;12(4):229   [PMID:  22378191 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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