title: Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.
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.
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Marco
authors: M
authors: Sciacovelli
authors: European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Cambridge CB10 1SD, UK.
authors: Emanuel
authors: E
authors: Gonçalves
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Timothy Isaac
authors: TI
authors: Johnson
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Vincent Roberto
authors: VR
authors: Zecchini
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Ana Sofia Henriques
authors: AS
authors: da Costa
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Edoardo
authors: E
authors: Gaude
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Alizee Vercauteren
authors: AV
authors: Drubbel
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Sebastian Julian
authors: SJ
authors: Theobald
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Sandra Riekje
authors: SR
authors: Abbo
authors: Department of Oncology, Uro-Oncology Research Group, University of Cambridge, Cambridge CB2 0Ql, UK.
authors: Maxine Gia Binh
authors: MG
authors: Tran
authors: 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.
authors: Vinothini
authors: V
authors: Rajeeve
authors: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
authors: Simone
authors: S
authors: Cardaci
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors: Sarah
authors: S
authors: Foster
authors: 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.
authors: Haiyang
authors: H
authors: Yun
authors: 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.
authors: Pedro
authors: P
authors: Cutillas
authors: Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK.
authors: Anne
authors: A
authors: Warren
authors: Academic Urology Group, Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.
authors: Vincent
authors: V
authors: Gnanapragasam
authors: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
authors: Eyal
authors: E
authors: Gottlieb
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
authors: Kristian
authors: K
authors: Franze
authors: 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.
authors: Brian
authors: B
authors: Huntly
authors: Department of Medical Genetics, University of Cambridge, Cambridge CB2 0QQ, UK.|NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
authors: Eamonn Richard
authors: ER
authors: Maher
authors: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors: Patrick Henry
authors: PH
authors: Maxwell
authors: European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute (EBI), Cambridge CB10 1SD, UK.|RWTH Aachen University, Faculty of Medicine, Joint Research Center for Computational Biomedicine, Aachen 52074, Germany.
authors: Julio
authors: J
authors: Saez-Rodriguez
authors: Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, UK.
authors: Christian
authors: C
authors: Frezza
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
chemical_list: D005650:Fumarates; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C032005:fumaric acid; D005649:Fumarate Hydratase