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

Abstract

Mutations of the tricarboxylic acid cycle (TCA cycle) enzyme fumarate hydratase (FH) cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)1. FH-deficient renal cancers are highly aggressive and metastasise even when small, leading to an abysmal clinical outcome2. Fumarate, a small molecule metabolite that accumulates in FH-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite3. Fumarate was shown to inhibit α-ketoglutarate (aKG)-dependent dioxygenases 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 FH and the subsequent accumulation of fumarate 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 FH-proficient cells with cell-permeable fumarate. Loss of FH is associated with suppression of miR-200 and EMT signature in renal cancer patients, and is associated with poor clinical outcome. These results imply that loss of FH and fumarate accumulation contribute to the aggressive features of FH-deficient tumours.

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…It has previously been shown that mutant IDH and D-2HG promote EMT in human colon cancer cells (30,37). Similarly, accumulation of fumarate in fumarate hydratase-deficient cells induces EMT through inhibition of a Tet-mediated demethylation process in the regulatory region of the miR-200ba429 cluster (51). We show that ADHFE1 and D-2HG have similar EMT-inducing effects in both breast cancer cells and benign breast epithelial cells.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…As such, the ac cu mu la tion of fu marate has been shown to di rectly pro mote onco genic post trans la tional mod i fi ca tions known as pro tein suc ci na tion [277]. Epi ge netic reg u la tion dic tated by metabo lite avail abil ity and in re la tion to the pe cu liar meta bolic al ter ations of can cer cells is also an emerg ing field of re search for the un der stand ing of the role of me tab o lism far be yond the do main of en ergy gen er a tion [220].…”

“…These metabo lites are able to in hibit α ke tog lu tarate de pen dent dioxy ge nases among which the afore men tioned HIF 1α neg a tive reg u la tor PHD2 [214][215][216], but also TET fam ily of 5 methyl cy to sine hy drox y lases and Ju monji fam ily of hi s tone demethy lases [217][218][219], as pre vi ously dis cussed in para graph 2. In hi bi tion of the last two re sults in DNA and hi s tone hy per me thy la tion which, in turn, re presses miR 200 ex pres sion [220,221] and/ or in duces EMT re lated tran scrip tion fac tors [220], lead ing to re pres sion of ep ithe lial mark ers, ex pres sion of mes enchy mal mark ers, and ac qui si tion of mi gra tory and in va sive traits [213,220,222,223].…”

An integrated computational and experimental study uncovers FUT 9 as a metabolic driver of colorectal cancer

“…Yet, only few metabolic genes are presently known to be directly implicated in tumorigenesis. Those include mutations/loss of the genes encoding succinate dehydrogenase (SDH) complex subunits, which may cause paraganglioma (Frezza et al , 2011), the inactivation and loss of fumarate hydratase (FH), playing a casual role in hereditary leiomyomatosis and renal cell cancer (HLRCC) (Kiuru et al , 2002), and mutations in IDH1 and IDH2, which can lead to low‐grade gliomas and acute myeloid leukemia (AML) (Parsons et al , 2008; Dang et al , 2009; Mardis et al , 2009; Sciacovelli et al , 2016; Sykes et al , 2016). Overall, there is still much more to learn about the causal role of metabolic genes in cancer.…”