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Nature. 2016 Aug 31;537(7621):544-547. doi: 10.1038/nature19353.

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.

Author information

1
Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
2
European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Cambridge CB10 1SD, UK.
3
Department of Oncology, Uro-Oncology Research Group, University of Cambridge, Cambridge CB2 0Ql, UK.
4
Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
5
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
6
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
7
Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke's Hospital, and Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0XY, UK.
8
Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK.
9
Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.
10
Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.
11
NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
12
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
13
RWTH Aachen University, Faculty of Medicine, Joint Research Center for Computational Biomedicine, Aachen 52074, Germany.

Abstract

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.

PMID:
27580029
PMCID:
PMC5136292
DOI:
10.1038/nature19353
[Indexed for MEDLINE]
Free PMC Article

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