IDH mutation impairs histone demethylation and results in a block to cell differentiation
Open accessAbstract
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.
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2-hydroxyglutarate interferes with iron-dependent hydroxylases, including the TET family of 5-methylcytosine hydroxylases.
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [6]
The paper’s Abstract (page unavailable) states that mutant IDH produces 2HG, reports mutant IDH-induced inhibition of the α-ketoglutarate-dependent enzyme TET2, and shows that 2HG inhibits a histone demethylase. It does not explicitly establish inhibition of the TET family as a whole or describe these enzymes as iron-dependent hydroxylases. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIncreased levels of 2-HG may enable a switch to an entirely HIF-independent mechanism.
“Therefore, it is plausible that increased levels of 2-HG may enable a switch to an entirely HIF-independent mechanism.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [154]
The passage labeled Abstract (page not provided) reports that 2-HG inhibits histone demethylation and can block cell differentiation, supporting a possible mechanism involving 2-HG. It does not address HIF or establish a switch to an entirely HIF-independent mechanism; searches for “HIF-independent mechanism” and “HIF hypoxia inducible factor” found no such passage. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMutant IDH protein generates the oncometabolite 2-hydroxyglutarate.
“Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [6]
D-2HG inhibits canonical metabolic enzymes, including transaminases that produce glutamate for glutathione biosynthesis, rendering IDH-mutant gliomas susceptible to treatments that deplete glutamate and enhance oxidative stress.
“In addition to its epigenetic effects, D-2HG inhibits enzymes from the canonical metabolic network (104). Such enzymes include transaminases that produce glutamate for glutathione biosynthesis, rendering IDH-mutant gliomas susceptible to treatments that deplete glutamate and enhance oxidative stress (105).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [104]
R-2-HG inhibits α-KG-dependent dioxygenases and demethylases.
“The role of R-2-HG as an oncometabolite has been implicated in epigenetic modifications through the inhibition of α-KG-dependent dioxygenases and demethylases”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [118]
Neomorphic IDH1/IDH2 mutations build up 2-HG, which blocks αKG-dependent enzymes like TET2, lowering 5hmC, raising DNA methylation, and changing gene expression to promote cancer.
“a neomorphic mutation in IDH1 and/or IDH2 causes a change in enzymatic activity and the accumulation of 2-hydroxyglutarate (2-HG), which inhibits the function of αKG-dependent enzymes such as TET2, resulting in the loss of 5hmC, an increase in DNA methylation and ultimately altered gene expression programmes that drive cancer development66.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [66]
By blocking the enzymatic activity of histone and DNA demethylases, d-2HG can lock cells in a hypermethylated state that blocks differentiation and reinforces a malignant and stem cell-like phenotype.
“By blocking the enzymatic activity of histone and DNA demethylases, d-2HG can function to lock cells in a hypermethylated state that blocks differentiation and reinforces a malignant and stem cell–like phenotype (30, 172, 173, 174).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [173]
In the cancer setting, 2-HG influences a number of biological processes, including cell differentiation, DNA methylation, and histone methylation.
“In the cancer setting, 2-HG has been shown to influence a number of biological processes, including cell differentiation, DNA methylation, and histone methylation (79–82), leading to its classification as an oncometabolite.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [80]
2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG, leading to reduced TET2 and JmjC activity in tumor cells.
“For example, 2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG (81, 99), leading to reduced TET2 and JmjC activity in tumor cells (79, 80).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [80]
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“Because IDH mutants block cell differentiation and promote tumor transformation, and inhibition of mutant IDH (IDHi) can reverse this effect, R-2HG (as the major metabolic product of IDH mutants) has been regarded as an oncometabolite (Figueroa et al., 2010; Lu et al., 2012; Rohle et al., 2013;Wang et al., 2013; Xu et…”
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- Authors
- Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., Wellen, K. E., O’Rourke, D. M., Berger, S. L., Chan, T. A., Levine, R. L., Mellinghoff, I. K., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Pennsylvania (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Nature
- Published
- 2012-02-15
- Volume
- 483
- Issue
- 7390
- Pages
- 474-478
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3478770
- OpenAlex
- W2154313451
- Cited by
- 1,985
- References
- 30
- Citations by year
- 2026: 81 · 2025: 93 · 2024: 106 · 2023: 125 · 2022: 122 · 2021: 180 · 2020: 170 · 2019: 153 · 2018: 146 · 2017: 163 · 2016: 151 · 2015: 123 · 2014: 138 · 2013: 136 · 2012: 91
- FWCI
- 74.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- University of Pennsylvania
- National Cancer Institute (R01CA078831, R01CA105463, U54CA143798)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- 2-hydroxyglutarate, histone demethylation, histone methylation, glioma, oncometabolites, DNA hypermethylation, hypoxia-inducible factor, adipogenesis, neural progenitor cells
- MeSH terms
- Animals, Astrocytes, Cell Differentiation, Enzyme Induction, Gene Expression Regulation, Glioma, Glutarates, Histones, Humans, Isocitrate Dehydrogenase, Methylation, Mutation, Promoter Regions, Genetic, Adipocytes, Cell Lineage, DNA Methylation, 3T3-L1 Cells, Cell Line, Tumor, Mice, Jumonji Domain-Containing Histone Demethylases, HEK293 Cells, Neural Stem Cells
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