Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes
Open accessAbstract
The TET enzymes are members of the 2-oxoglutarate-dependent dioxygenase family and comprise three isoenzymes in humans: TETs 1-3. These TETs convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC) in DNA, and high 5-hmC levels are associated with active transcription. The importance of the balance in these modified cytosines is emphasized by the fact that TET2 is mutated in several human cancers, including myeloid malignancies such as acute myeloid leukemia (AML). We characterize here the kinetic and inhibitory properties of Tets and show that the Km value of Tets 1 and 2 for O2 is 30 μm, indicating that they retain high activity even under hypoxic conditions. The AML-associated mutations in the Fe(2+) and 2-oxoglutarate-binding residues increased the Km values for these factors 30-80-fold and reduced the Vmax values. Fumarate and succinate, which can accumulate to millimolar levels in succinate dehydrogenase and fumarate hydratase-mutant tumors, were identified as potent Tet inhibitors in vitro, with IC50 values ∼400-500 μm. Fumarate and succinate also down-regulated global 5-hmC levels in neuroblastoma cells and the expression levels of some hypoxia-inducible factor (HIF) target genes via TET inhibition, despite simultaneous HIFα stabilization. The combination of fumarate or succinate treatment with TET1 or TET3 silencing caused differential effects on the expression of specific HIF target genes. Altogether these data show that hypoxia-inducible genes are regulated in a multilayered manner that includes epigenetic regulation via TETs and 5-hmC levels in addition to HIF stabilization.
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High fumarate inhibits TET enzymes, stimulating EMT and leading to cancer metastasis.
“In addition, fumarate inhibits TET enzymes, which stimulate EMT, leading to cancer metastasis131,132.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [132]
Germline mutations in L2HGDH and D2HGDH cause L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria.
“The cause of these so-called 2-hydroxyglutaric acidurias (2HGAs) was attributed to germline mutations in L-2-HG dehydrogenase (L2HGDH) and D-2-HG dehydrogenase (D2HGDH), the mitochondrial enzymes responsible for the conversion of 2-HG to α-KG and thus its breakdown107-109.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [108]
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- Authors
- Laukka, T., Mariani, C. J., Ihantola, T., Cao, J. Z., Hokkanen, J., Kaelin, W. G., Godley, L. A., & Koivunen, P.
- Affiliations
- University of Oulu (FI)
- University of Chicago (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Koivunen, Peppi
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 291
- Issue
- 8
- Pages
- 4256-4265
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4759199
- OpenAlex
- W2210628912
- Cited by
- 307
- References
- 39
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 27 · 2023: 28 · 2022: 38 · 2021: 35 · 2020: 29 · 2019: 36 · 2018: 25 · 2017: 33 · 2016: 13
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Suomen Akatemia (120156, 140765, 218129, 266719)
- Sigrid Juséliuksen Säätiö
- Emil Aaltosen Säätiö
- Jane ja Aatos Erkon Säätiö
- Syöpäjärjestöt
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- TET enzymes, fumarate, succinic acid, 5-hydroxymethylcytosine, 5-methylcytosine, hypoxia-inducible factor, HIF target genes, acute myeloid leukemia, TET2 mutation, 2-oxoglutarate-dependent dioxygenase, enzyme kinetics, succinate dehydrogenase, fumarate hydratase, epigenetic regulation, neuroblastoma, TET1, TET3
- MeSH terms
- Animals, DNA-Binding Proteins, Fumarates, Humans, Mixed Function Oxygenases, Mutation, Neuroblastoma, Proto-Oncogene Proteins, Leukemia, Myeloid, Acute, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Succinic Acid, Cell Line, Tumor, Dioxygenases, Mice
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