The emerging role of fumarate as an oncometabolite
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The drive to understand how altered cellular metabolism and cancer are linked has caused a paradigm shift in the focus of cancer research. The discovery of a mutated metabolic enzyme, isocitrate dehydrogenase 1, that leads to accumulation of the oncometabolite 2-hydroxyglutarate, provided significant direct evidence that dysfunctional metabolism plays an important role in oncogenesis. Striking parallels exist with the Krebs cycle enzyme fumarate hydratase (FH), a tumor suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumors. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. Interestingly, our studies have questioned the role of HIF and have highlighted other candidate mechanisms, in particular the non-enzymatic modification of cysteine residues (succination) that could lead to disruption or loss of protein functions, dysfunctional cell metabolism and cell signaling. Here, we discuss the evidence for proposing fumarate as an onco-metabolite.
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A third 2HGA arises from germline mutations in SLC25A1, in which both enantiomers accumulate.
“A third 2HGA that arises from germline mutations in the mitochondrial citrate carrier SLC25A1, in which both enantiomers accumulate, has also been discovered.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [111]
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- Authors
- Yang, M., Soga, T., Pollard, P. J., & Adam, J.
- Affiliations
- University of Oxford (GB)
- Keio University (JP)
- Corresponding author
- Pollard, Patrick J.
- Venue
- Frontiers in Oncology
- Publisher
- Frontiers Media SA
- Published
- 2012
- Volume
- 2
- Pages
- 85-85
- ISSN
- 2234-943X (ISSN-L)
- PMC
- PMC3408580
- OpenAlex
- W2167537549
- Cited by
- 189
- References
- 63
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 12 · 2022: 24 · 2021: 18 · 2020: 18 · 2019: 18 · 2018: 16 · 2017: 10 · 2016: 10 · 2015: 9 · 2014: 10 · 2013: 9 · 2012: 1
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust
- Cancer Research UK
- Keio University
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- fumarate, oncometabolites, fumarate hydratase, IDH1, 2-hydroxyglutarate, 2-oxoglutarate-dependent dioxygenase, cysteine modification, cancer metabolism, tumor suppressor, TCA cycle
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