Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer.
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.
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Hugh
H
Colvin
Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Naohiro
N
Nishida
Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Masamitsu
M
Konno
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Naotsugu
N
Haraguchi
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Hidekazu
H
Takahashi
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Junichi
J
Nishimura
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Taishi
T
Hata
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Koichi
K
Kawamoto
Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Ayumu
A
Asai
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Taiho Pharmaceutical Co., Ltd., Chiyoda-ku, Tokyo, 101-0054, Japan.
Kenta
K
Tsunekuni
Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Jun
J
Koseki
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Tsunekazu
T
Mizushima
Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Taroh
T
Satoh
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Yuichiro
Y
Doki
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Masaki
M
Mori
Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.|Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Hideshi
H
Ishii
D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005973:Glutamine / Q000378:metabolism*; D005977:Glutarates / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D009154:Mutation; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism
D005977:Glutarates; D006657:Histones; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D005973:Glutamine; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase