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

Marco Sciacovelli, Emanuel Gonçalves, Timothy Isaac Johnson, Vincent Roberto Zecchini, Ana Sofia Henriques da Costa, Edoardo Gaude, Alizee Vercauteren Drubbel, Sebastian Julian Theobald, Sandra Riekje Abbo, Maxine Gia Binh Tran, Vinothini Rajeeve, Simone Cardaci, Sarah Foster, Haiyang Yun, Pedro Cutillas, Anne Warren, Vincent Gnanapragasam, Eyal Gottlieb, Kristian Franze, Brian HuntlyEamonn Richard Maher, Patrick Henry Maxwell, Julio Saez-Rodriguez, Christian Frezza

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)544-547
Number of pages4
JournalNature
Volume537
Issue number7621
DOIs
Publication statusPublished - 31 Aug 2016

Keywords

  • Animals
  • Cell Movement
  • Cells, Cultured
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition
  • Fumarate Hydratase/deficiency
  • Fumarates/metabolism
  • HEK293 Cells
  • Humans
  • Kidney Neoplasms/genetics
  • Mesoderm/metabolism
  • Mice
  • MicroRNAs/genetics
  • Transcription Factors/metabolism
  • Transcriptome

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