大腸癌における代謝産物２－Ｈｙｄｒｏｘｙｇｌｕｔａｒａｔｅの臨床的意義の解明

阐明代谢物 2-羟基戊二酸在结直肠癌中的临床意义

• 批准号: 16J09684
• 负责人: COLVIN HUGH SHUNSUKE
• 金额: $ 0.83万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2016
• 资助国家: 日本
• 起止时间: 2016-04-22 至 2018-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16J09684/
• 关键词: Colorectal Cancer; D-2-hydroxyglutarate; L-2-hydroxyglutarate; Oncometabolite; EMT; Metastasis

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.

精神错乱的代谢是癌症的标志，在驱动疾病过程中发挥了重要作用。这样的例子是通过oncometabolite D-2羟基戊二酸（D-2HG）诱导致癌作用，该羟基戊二酸（D-2HG）是由突变的异位酸酶脱氢酶（IDH）产生的，发生在白血病和脑肿瘤的亚群中。 D-2HG的致癌特性似乎源于其干扰 - 酮酸盐依赖性双氧酶的活性，包括Jumonji家族组蛋白脱甲基酶。在这里，我们在结直肠癌细胞中发现，即使在没有IDH突变的情况下，D-2HG及其对映体L-2HG的水平也通过谷氨酰胺衰减升高。 D-2HG而不是L-2HG增加了Zeb1启动子区域的组蛋白H3赖氨酸4的三甲基化，这是上皮 - 间质转变（EMT）的主要调节剂（EMT），并增加了Zeb1基因直接诱导Colorectal Cancelal Callictal Callictal Cancelal Callical Callictal Callical Callical Callical Callical Callical Callice细胞中EMT的表达。 EMT促进了癌细胞侵入局部组织并进入血液的能力，从而导致远处的器官转移。大肠癌标本中的D-2HG水平升高，尤其是与远处转移相关的标本，支持体外观察结果，并暗示了D-2HG在转移中的贡献，这是该疾病中主要死亡的主要原因。

项目成果

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

• DOI: 10.1038/srep36289
• 发表时间: 2016-11-08
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Colvin H;Nishida N;Konno M;Haraguchi N;Takahashi H;Nishimura J;Hata T;Kawamoto K;Asai A;Tsunekuni K;Koseki J;Mizushima T;Satoh T;Doki Y;Mori M;Ishii H
• 通讯作者: Ishii H

2-Hydroxyglurate Induces Epithelial-Mesenchymal Transition Through Histone Modifications in Colorectal Cancer Cells

2-羟基戊二酸通过组蛋白修饰诱导结直肠癌细胞的上皮-间质转化

• 发表时间: 2016
• 作者: Hugh Colvin;Naohiro Nishida;Jun Koseki;Masamitsu Konno;Koichi Kawamoto;Yuichiro Doki;Masaki Mori;Hideshi Ishii
• 通讯作者: Hideshi Ishii