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

延胡索酶 富马酸二甲酯 癌症研究 表观遗传学 DNA去甲基化 化学 上皮-间质转换 生物 生物化学 DNA甲基化 基因表达 过渡(遗传学) 基因 免疫学 多发性硬化
作者
Marco Sciacovelli,Henning Schmidt,Timothy Isaac Johnson,Vincent Zecchini,Ana S.H. Costa,Edoardo Gaude,Alizée Vercauteren Drubbel,Sebastian J. Theobald,Sandra Riekje Abbo,Maxine Tran,Vinothini Rajeeve,Simone Cardaci,Sarah Foster,Haiyang Yun,Pedro R. Cutillas,Anne Y. Warren,Vincent J. Gnanapragasam,Eyal Gottlieb,Kristian Franze,Brian J.P. Huntly,Eamonn R. Maher,Patrick H. Maxwell,Julio Sáez-Rodríguez,Christian Frezza
出处
期刊:Nature [Nature Portfolio]
卷期号:537 (7621): 544-547 被引量:464
标识
DOI:10.1038/nature19353
摘要

Accumulation of fumarate resulting from mutations in fumarate hydratase,which are associated with renal and other cancers, is shown to induce epithelial-to-mesenchymal transition—a process associated with cancer initiation. 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.
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