TY - JOUR
T1 - Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition
AU - Sciacovelli, Marco
AU - Gonçalves, Emanuel
AU - Johnson, Timothy Isaac
AU - Zecchini, Vincent Roberto
AU - da Costa, Ana Sofia Henriques
AU - Gaude, Edoardo
AU - Drubbel, Alizee Vercauteren
AU - Theobald, Sebastian Julian
AU - Abbo, Sandra Riekje
AU - Tran, Maxine Gia Binh
AU - Rajeeve, Vinothini
AU - Cardaci, Simone
AU - Foster, Sarah
AU - Yun, Haiyang
AU - Cutillas, Pedro
AU - Warren, Anne
AU - Gnanapragasam, Vincent
AU - Gottlieb, Eyal
AU - Franze, Kristian
AU - Huntly, Brian
AU - Maher, Eamonn Richard
AU - Maxwell, Patrick Henry
AU - Saez-Rodriguez, Julio
AU - Frezza, Christian
PY - 2016/8/31
Y1 - 2016/8/31
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Movement
KW - Cells, Cultured
KW - Epigenesis, Genetic
KW - Epithelial-Mesenchymal Transition
KW - Fumarate Hydratase/deficiency
KW - Fumarates/metabolism
KW - HEK293 Cells
KW - Humans
KW - Kidney Neoplasms/genetics
KW - Mesoderm/metabolism
KW - Mice
KW - MicroRNAs/genetics
KW - Transcription Factors/metabolism
KW - Transcriptome
UR - https://www.nature.com/articles/nature19353
U2 - 10.1038/nature19353
DO - 10.1038/nature19353
M3 - Article
C2 - 27580029
SN - 0028-0836
VL - 537
SP - 544
EP - 547
JO - Nature
JF - Nature
IS - 7621
ER -