IDH mutation impairs histone demethylation and results in a block to cell differentiation

By Chao Lu, Patrick S. Ward, G. Kapoor, D. Rohle, Şevin Turcan, O. Abdel-Wahab, C. Edwards, Raya Khanin, Maria E. Figueroa, A. Melnick and 7 more. Nature, 2012

1,923 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f4232ea12310ab3a49c0e7438f12d1aa94c6dca4

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Citations in the corpus

Durable Remissions with Ivosidenib in IDH1‐Mutated Relapsed or Refractory AML (2018, neutral): “Dose-escalation phase 2/33 (6) 2/35 (6) 3/78 (4)”
Revisiting the hallmarks of cancer. (2017, neutral): “This subsequently inhibits dioxygenases with hypermethylation silencing of an array of genes that may contribute to cancer progression [162-164].”
Glioma Subclassifications and Their Clinical Significance (2017, neutral): “likely other contributing mechanisms [16, 17].”
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity (2016, background): “KDMs of the JmjC and JmjD family need a-ketoglutarate as a cofactor for the demethylation process (Lu et al., 2012), whereas metabolites with a similar molecular structure, such as fumarate, can act as antagonizing factors (Lu et al., 2012; Xiao et al., 2012), thereby inhibiting demethylation.”
Epigenetic Determinants of Cancer. (2016, background): “appear to alter the DNA and histone demethylation pathways, resulting in imbalances in histone methylation levels, such as increases in H3K36, H3K9 methylation (Lu et al. 2012; Lu et al. 2013; Venneti et al. 2013).”
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma (2017, neutral): “…IDH1 and/or IDH2 (IDH1/2) mutations and exhibited a distinct DNA hypermethylation profile (Figure 2A), consistent with previous data that IDH1/2 mutations are gain-of-function lesions that increase levels of cellular D-2-hydroxyglutarate that regulate genomic methylation rates (Lu et al., 2012).”
Targeting Suppressor of Variegation 3-9 Homologue 2 (SUV39H2) in Acute Lymphoblastic Leukemia (ALL) (2015, background): “demethylases such as KDM4C, has been found to inhibit differentiation of hematopoietic cells [27].”
The role of mutations in epigenetic regulators in myeloid malignancies (2012, background): “Not only is DNA methylation is altered in IDH1/2-mutant cells; 2-HG levels also increase levels of histone lysine di- and trimethylation marks due to impaired histone demethylation (62).”
Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma (2013, background): “These observations, taken together with previous studies showing requirement of extended passages for the induction of the G-CIMP phenotype by IDH1 mutation (Lu et al., 2012; Turcan et al., 2012), favor a model in which a majority of undifferentiated GSCs already exist in a PN/CIMP state and are sel”
The Warburg Effect Dictates the Mechanism of Butyrate Mediated Histone Acetylation and Cell Proliferation (2012, background): “This idea is supported by recent reports showing that the oncometabolite 2-hydroxyglutarate, which accumulates in tumors as a result of isocitrate dehydrogenase (IDH1/2) mutations, inhibits JmjC histone demethylases and DNA methyltransferses to alter the transcription of genes necessary for differen”