title: IDH mutation impairs histone demethylation and results in a block to cell differentiation.
abstract: 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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Ward
authors.forename: Gurpreet S
authors.initials: GS
authors.lastname: Kapoor
authors.forename: Dan
authors.initials: D
authors.lastname: Rohle
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Edwards
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
authors.forename: Donald M
authors.initials: DM
authors.lastname: O'Rourke
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005977:Glutarates / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009154:Mutation / Q000235:genetics*; D058953:Neural Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D005977:Glutarates; D006657:Histones; C413655:KDM4C protein, human; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; D056484:Jumonji Domain-Containing Histone Demethylases