Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer

Abstract

Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases. Here, we find in colorectal cancer cells that even in the absence of IDH mutation, the levels of D-2HG and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1, a master regulator of epithelial-mesenchymal transition (EMT), and increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. EMT promotes the ability of cancer cells to invade the local tissue and enter into the bloodstream, leading to distant organ metastasis. D-2HG levels were elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…A key finding of our study is the discovery that both ADHFE1 and D-2HG similarly induce EMT, stemness, and invasion of mammary cells. 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).…”

“…2HG inhibits histone lysine demethylases, which can lead to increased methylation of histones (28,29). It was shown that D-2HG increases trimethylation of histone H3 lysine 4 (H3K4me3) in the promoter region of the EMT regulator, ZEB1, in HCT116 colorectal cancer cells (30). Increased EMT.…”

“…While there are numerous reports studying the mechanisms of IDH-dependent D-2HG accumulation in mammalian cells, few explored aberrant D-2HG accumulation in the absence of mutant IDH (30,44,45). In one study, it was shown that phosphoglycerate dehydrogenase (PHGDH) produces D-2HG (44), although the reported increase in D-2HG in breast cancer cell lines due to PHG-DH was modest (2-to 3-fold), and by itself would not explain a 10-to 100-fold accumulation of D-2HG in some breast tumors.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…in acute myeloid leukemia and glioblas toma [211,212], al though sig nif i cant lev els of this on cometabo lite were also de tected in colon car ci noma cell lines in de pen dently of any mu ta tion [213]. 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.…”

“…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].…”