Oncometabolite D-2-Hydroxyglutarate enhances gene silencing through inhibition of specific H3K36 histone demethylases
Open accessAbstract
Certain mutations affecting central metabolism cause accumulation of the oncometabolite D-2-hydroxyglutarate which promotes progression of certain tumors. High levels of D-2-hydroxyglutarate inhibit the TET family of DNA demethylases and Jumonji family of histone demethylases and cause epigenetic changes that lead to altered gene expression. The link between inhibition of DNA demethylation and changes in expression is strong in some cancers, but not in others. To determine whether D-2-hydroxyglutarate can affect gene expression through inhibiting histone demethylases, orthologous mutations to those known to cause accumulation of D-2-hydroxyglutarate in tumors were generated in Saccharomyces cerevisiae, which has histone demethylases but not DNA methylases or demethylases. Accumulation of D-2-hydroxyglutarate caused inhibition of several histone demethylases. Inhibition of two of the demethylases that act specifically on histone H3K36me2,3 led to enhanced gene silencing. These observations pinpointed a new mechanism by which this oncometabolite can alter gene expression, perhaps repressing critical inhibitors of proliferation.
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D-2HG can accumulate to millimolar levels in cancer cells expressing mutant IDH and at these concentrations inhibits alpha-ketoglutarate-dependent dioxygenases, including enzymes involved in histone and DNA demethylation.
“Though it is found at low levels in normal cells, D-2HG can accumulate to millimolar levels in cancer cells expressing mutant IDH. At these high concentrations, D-2HG can inhibit αKG-dependent dioxygenases, including enzymes involved in histone and DNA demethylation (Chowdhury et al., 2011; Janke et al., 2017; Koivunen et al., 2012; Xu et al., 2011).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Janke et al., 2017
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References 42 · Cited by 40
- Authors
- Janke, R., Iavarone, A. T., & Rine, J.
- Affiliations
- QB3 (US)
- Corresponding author
- Rine, Jasper
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-03-27
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5388528
- OpenAlex
- W2600646132
- Cited by
- 40
- References
- 42
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 4 · 2017: 3
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (F32 Postdoctoral Fellowship, GM115074, 1S10OD020062-01, GM31105, GM120374)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- D-2-hydroxyglutarate, oncometabolites, histone demethylase, H3K36me2, H3K36me3, gene silencing, DNA demethylation, epigenetic regulation, Saccharomyces cerevisiae, tumor progression
- MeSH terms
- Glutarates, Histones, Protein Processing, Post-Translational, Saccharomyces cerevisiae, Gene Silencing, Saccharomyces cerevisiae Proteins, Histone Demethylases
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