Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition
Open accessAbstract
Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.
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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 [131]
Restoring fumarate hydratase function in tumor cells causes loss of ability to invade and migrate.
“Further confirmation of fumarate as an oncometabolite was verified by experimental data showing that tumor cells lost their ability to invade and migrate when the function of fumarate hydratase was restored by an external expression vector131.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [131]
Mutations in IDH1/2 are the most frequently mutated metabolic genes in human cancer.
“In recent years, two landmark genomic studies carried out in human glioma and acute myeloid leukaemia (AML) found mutations in IDH1/2 and it is now appreciated that these enzymes (which drive elevated production of D-2-HG) are the most frequently mutated metabolic genes in human cancer112-114.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [112]
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Self-citation
- Authors
- Sciacovelli, M., Gonçalves, E., Johnson, T. I., Zecchini, V. R., da Costa, A. S. H., Gaude, E., Drubbel, A. V., Theobald, S. J., Abbo, S. R., Tran, M. G. B., Rajeeve, V., Cardaci, S., Foster, S., Yun, H., Cutillas, P., Warren, A., Gnanapragasam, V., Gottlieb, E., Franze, K., Huntly, B., Maher, E. R., Maxwell, P. H., Saez-Rodriguez, J., & Frezza, C.
- Affiliations
- University of Cambridge (GB)
- European Bioinformatics Institute (GB)
- Queen Mary University of London (GB)
- Cancer Research UK Scotland Institute (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Corresponding author
- Frezza, Christian
- ORCID
- Sciacovelli, Marco
- Gonçalves, Emanuel
- Johnson, Timothy Isaac
- Zecchini, Vincent Roberto
- Gaude, Edoardo
- Tran, Maxine Gia Binh
- Rajeeve, Vinothini
- Cardaci, Simone
- Yun, Haiyang
- Cutillas, Pedro
- Warren, Anne
- Gnanapragasam, Vincent
- Gottlieb, Eyal
- Franze, Kristian
- Huntly, Brian
- Maher, Eamonn Richard
- Maxwell, Patrick Henry
- Frezza, Christian
- Venue
- Nature
- Published
- 2016-08-31
- Volume
- 537
- Issue
- 7621
- Pages
- 544-547
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5136292
- OpenAlex
- W2513105811
- Cited by
- 584
- References
- 40
- Citations by year
- 2026: 56 · 2025: 49 · 2024: 61 · 2023: 54 · 2022: 64 · 2021: 60 · 2020: 56 · 2019: 59 · 2018: 55 · 2017: 55 · 2016: 14
- FWCI
- 25.67
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-10-19)
- Open access
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (096956/Z/11/Z)
- Cancer Research UK (18278)
- National Institute for Health and Care Research (NF-SI-0514-10122)
- Medical Research Council (MC_PC_12009, MR/M010392/1, MC_UU_12022/6)
- Cancer Research UK Cambridge Institute, University of Cambridge
- National Cancer Institute
- 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 › Chromatin Remodeling and Cancer
- Keywords
- fumarate, fumarate hydratase, epithelial-mesenchymal transition, oncometabolites, TCA cycle, DNA demethylation, histone demethylation, alpha-ketoglutarate-dependent dioxygenase, miR-200 family, miR-429, metastasis, renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma, cell migration, epigenetic modifications
- MeSH terms
- Animals, Cell Movement, Cells, Cultured, Fumarate Hydratase, Fumarates, Humans, Kidney Neoplasms, Mesoderm, Transcription Factors, MicroRNAs, Epigenesis, Genetic, Mice, HEK293 Cells, Epithelial-Mesenchymal Transition, Transcriptome
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