2016 Fiscal Year Annual Research Report
大腸癌における代謝産物２－Ｈｙｄｒｏｘｙｇｌｕｔａｒａｔｅの臨床的意義の解明
| Project/Area Number |
16J09684
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| Research Institution | Osaka University |
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Principal Investigator |
COLVIN HUGH SHUNSUKE 大阪大学, 医学系研究科, 特別研究員(DC2)
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| Project Period (FY) |
2016-04-22 – 2018-03-31
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| Keywords | Colorectal Cancer / D-2-hydroxyglutarate / L-2-hydroxyglutarate / Oncometabolite / EMT / Metastasis |
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| Outline of Annual Research Achievements |
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 -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.
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| Research Progress Status |
翌年度、交付申請を辞退するため、記入しない。
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| Strategy for Future Research Activity |
翌年度、交付申請を辞退するため、記入しない。
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[Journal Article] Oncometabolite D-2-Hydroxyglutarate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer.2016
Author(s)
Hugh Colvin, Naohiro Nishida, Masamitsu Konno, Naotsugu Haraguchi, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Koichi Kawamoto, Ayumu Asai, Kenta Tsunekuni, Jun Koseki, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori & Hideshi Ishii
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Journal Title
Scientific Reports
Volume: 6
Pages: 36289
DOI
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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