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

Sciacovelli, M. et al. (2016) Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature, 537(7621), pp. 544-547. (doi: 10.1038/nature19353) (PMID:27580029) (PMCID:PMC5136292)

Abstract

Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer1. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome2. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite3. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation4, 5. 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 metastasis6. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster6 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.

• Item Type: Articles (Letter)
• Additional Information: This work was supported by the Medical Research Council (UK). S.F. was supported by a Herchel Smith Research Studentship and K.F. by an MRC Career Development Award. E.R.M is supported by the ERC Advanced Researcher award 323004–ONCOTREAT. P.H.M. is supported by Senior Investigator Awards from the Wellcome Trust and NIHR. The Cambridge Human Research Tissue Bank and A.W. are supported by the NIHR Cambridge Biomedical Research Centre.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cardaci, Dr Simone and Gottlieb, Professor Eyal
• 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., and Frezza, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 31 August 2016
• Copyright Holders: Copyright © 2016 Macmillan Publishers Limited
• First Published: First published in Nature 537(7621): 544-547
• Publisher Policy: Reproduced in accordance with the publisher copyright policy