Abstract
FH depletion promotes EMT via fumarate-dependent epigenetic downregulation of miR-200ba429.
Major finding: FH depletion promotes EMT via fumarate-dependent epigenetic downregulation of miR-200ba429.
Mechanism: Fumarate accumulation represses TET-mediated demethylation of a miR-200ba429 regulatory CpG island.
Impact: The aggressiveness of FH-deficient tumors may result from fumarate-dependent enhancement of EMT.
Fumarate is a metabolite of the tricarboxylic acid cycle that also inhibits α-ketoglutarate–dependent dioxygenases such as TET enzymes involved in DNA demethylation and has been shown to promote cellular transformation. Mutations in fumarate hydratase (FH), which catalyzes the conversion of fumarate to malate, result in fumarate accumulation and are associated with aggressive renal cell cancers with poor clinical outcomes. To discover how loss of FH promotes tumorigenesis, Sciacovelli and colleagues analyzed the proteome and transcriptome of FH-deficient cells and found that vimentin was overexpressed. Vimentin is a marker of epithelial-to-mesenchymal transition (EMT), and, accordingly, reintroduction of FH reduced vimentin expression, increased expression of the epithelial marker E-cadherin, promoted an epithelial morphology, and suppressed cell motility, altogether indicating that FH loss may promote EMT. Moreover, several key EMT transcription factors were upregulated in FH-deficient cells, including SNAI2, ZEB1, and ZEB2, which are known to be suppressed by antimetastatic miRNAs in the miR-200ba429 miRNA cluster, which includes miR-200a, miR-200b, and miR-429 and was also downregulated in FH-deficient cells. miR-200 expression can be repressed by CpG island hypermethylation, and fumarate suppressed TET activity, resulting in increased methylation of the regulatory CpG43 CpG island of miR-200ba429 and reduced miR-200ba429 expression. Consistent with these findings, in patients with renal cancer, loss of FH was associated with an EMT signature with high expression of vimentin and low expression of E-cadherin and reduced patient survival. These results suggesting that fumarate accumulation may promote EMT by epigenetic downregulation of an antimetastatic miRNA cluster provide insight into the etiology of FH-deficient tumors.
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