Sciacovelli M, Goncalves E, Johnson TI, Zecchini VR, Da Costa ASH, Gaude E, Drubbel AV, Theobald SJ, Abbo SR, Tran MGB, Rajeeve V, Cardaci S, Foster S, Yun H, Cutillas P, Warren A, Gnanapragasam V, Gottlieb E, Franze K, Huntly B, Maher ER, Maxwell PH, Saez-Rodriguez J, Frezza C (2016)
Publication Type: Journal article
Publication year: 2016
Book Volume: 537
Pages Range: 544-547
Journal Issue: 7621
DOI: 10.1038/nature19353
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.
APA:
Sciacovelli, M., Goncalves, E., Johnson, T.I., Zecchini, V.R., Da Costa, A.S.H., Gaude, E.,... Frezza, C. (2016). Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature, 537(7621), 544-547. https://doi.org/10.1038/nature19353
MLA:
Sciacovelli, Marco, et al. "Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition." Nature 537.7621 (2016): 544-547.
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