Editors' ChoiceCancer

One way fumarate can promote metastasis

Sci. Signal.  27 Sep 2016:
Vol. 9, Issue 447, pp. ec221
DOI: 10.1126/scisignal.aak9768

Mutations that affect the tricarboxylic acid cycle enzyme fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell cancer (HLRCC), which is characterized by benign tumors in various tissues and an increased risk for developing aggressive, metastatic renal cancers. When FH activity is absent or reduced, cells accumulate the metabolite fumarate, which can inhibit dioxygenases that participate in DNA and histone methylation. From proteomic and gene expression analyses, Sciacovelli et al. found that proteins and transcripts involved in the epithelial-to-mesenchymal transition (EMT) were more abundant in Fh1–/– mouse cells and UOK262 cells, an immortalized human Fh1–/– cell line derived from an HLRCC patient, than in control cells. Transgenic expression of Fh1 reversed this EMT signature, restored epithelial polarity, and reduced cell motility. Treating control cells with the cell-permeable fumarate derivative monomethyl fumarate (MMF) induced a mesenchymal phenotype. Fh1–/– cells also exhibited decreased abundance of microRNAs (miRNAs) of the miR-200 family, which was rescued by expression of Fh1. Members of the miR-200 family are abundant in epithelial tissues and suppress the expression of genes associated with EMT, and aberrant methylation of the miR-200 promoter is associated with metastasis of epithelial cancers. Knocking down Tet2 and Tet3, which encode methylcytosine dioxygenases that participate in DNA demethylation, also reduced miR-200 expression and promoted EMT in control cells. The miR-200 promoter contains Tet binding sites and was hypermethylated in Fh1–/– cells and in MMF-treated control cells, suggesting that fumarate inhibits the Tet-dependent demethylation of the miR-200 promoter. In tumor samples from HLRCC patients and other patients with tumors containing mutations in Fh1, the reduced abundance of FH correlated with increased expression of EMT markers, reduced expression of miR-200A and miR-200B, hypermethylation of the miR-200 promoter, and poor prognosis. The authors propose a model in which the accumulation of fumarate inhibits Tet, thereby silencing the expression of miR-200 and inducing EMT, leading to metastasis.

M. Sciacovelli, E. Gonçalves, T. I. Johnson, V. R. Zecchini, A. S. H. da Costa, E. Gaude, A. V. Drubbel, S. J. Theobald, S. R. Abbo, M. G. B. Tran, V. Rajeeve, S. Cardaci, S. Foster, H. Yun, P. Cutillas, A. Warren, V. Gnanapragasam, E. Gottlieb, K. Franze, B. Huntly, E. R. Maher, P. H. Maxwell, J. Saez-Rodriguez, C. Frezza. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544–547 (2016). [PubMed]

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