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Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
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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.
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“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 [152]
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In the citing paper
“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 [5]
The cited source says what the claim attributes to it.
In the citing paper
“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 [5]
In the citing paper
“The observation that IDH1 and IDH2 mutations can partially phenocopy the loss of TET function may explain the mutual exclusivity of these mutations in cancer 95,97 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [97]
In the citing paper
“Mutant IDH protein is a competitive inhibitor of hydroxylases, including the TET family of 5mC hydroxylases120–122.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [122]
In the citing paper
“These observations support a model in which PU.1 guides TET2 to a specific subset of genomic regions to facilitate the oxidation of 5mC to 5hmC, a reaction that is inhibited by 2-hydroxyglutarate47 and enhanced by vitamin C13 (Figure 5d).”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [47]
In the citing paper
“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 [81]
In the citing paper
“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 [81]
In the citing paper
“Furthermore, TH17 cell differentiation could be initiated by exogenous addition of D-2-HG to naïve CD4+ T cells or by genetic silencing of TET1 and TET2, established targets of 2-HG143-145.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [145]
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Metadata
- Authors
- Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., Liu, L.-X., Jiang, W.-Q., Liu, J., Zhang, J.-Y., Wang, B., Frye, S., Zhang, Y., Xu, Y.-H., Lei, Q.-Y., Guan, K.-L., Zhao, S.-M., & Xiong, Y.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- University of North Carolina at Chapel Hill (US)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Guan, Kun-Liang
- Xiong, Yue
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 19
- Issue
- 1
- Pages
- 17-30
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3229304
- OpenAlex
- W2131860315
- Cited by
- 2,875
- References
- 55
- Citations by year
- 2026: 165 · 2025: 168 · 2024: 192 · 2023: 182 · 2022: 183 · 2021: 270 · 2020: 214 · 2019: 191 · 2018: 195 · 2017: 183 · 2016: 196 · 2015: 180 · 2014: 183 · 2013: 157 · 2012: 137
- FWCI
- 90.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 928 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Natural Science Foundation of China (11079016, 30600112, 30871255, 30971485/C0706)
- Ministry of Education of the People's Republic of China
- National Key Research and Development Program of China (2011CB910600, 2011CB965300)
- Project 985
- Major State Basic Research Development Program of China (2009CB918401, 2009CB918600)
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- 2-hydroxyglutarate, oncometabolites, alpha-ketoglutarate-dependent dioxygenase, IDH1 mutation, IDH2 mutation, histone demethylase, 5-hydroxymethylcytosine, competitive inhibition, glioma, acute myeloid leukemia, DNA methylation, histone methylation, active site
- MeSH terms
- Animals, Binding, Competitive, Cytosine, DNA-Binding Proteins, Glioma, Glutarates, Histones, Humans, Mixed Function Oxygenases, Isocitrate Dehydrogenase, Ketoglutaric Acids, Models, Molecular, Oxalates, Oxidoreductases, N-Demethylating, Procollagen-Proline Dioxygenase, Proto-Oncogene Proteins, Gene Expression, Caenorhabditis elegans, Homeodomain Proteins, Amino Acid Substitution, Catalytic Domain, Caenorhabditis elegans Proteins, Endostatins, 5-Methylcytosine, F-Box Proteins, Cell Line, Tumor, Dioxygenases, Hypoxia-Inducible Factor 1, alpha Subunit, Biocatalysis, Histone Demethylases, Jumonji Domain-Containing Histone Demethylases, Hypoxia-Inducible Factor-Proline Dioxygenases
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