Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer.
Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer.
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DOI：
10.1038/srep36289
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发表时间：
2016-11-08
影响因子：
4.6
通讯作者：
Ishii H
中科院分区：
文献类型：
--
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
代谢紊乱是癌症的一个标志，在推动疾病进程中发挥着重要作用。一个这样的例子是由肿瘤代谢物D-2羟基戊二酸(D-2HG)诱导致癌，它是由白血病和脑瘤亚群中出现的突变酶异柠檬酸脱氢酶(IDH)产生的。D-2HG的致癌特性似乎源于它能够干扰依赖于α的酮戊二酸双加氧酶的活性，包括Jumonji家族的组蛋白去甲基酶。在此，我们发现在大肠癌细胞中，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逆转而升高。D-2HG，而不是L-2HG，增加了ZEB1启动子区域组蛋白H3赖氨酸4的三甲基化，并增加了ZEB1基因的表达，直接诱导结直肠癌细胞发生上皮-间充质转化。EMT促进癌细胞侵入局部组织并进入血流，导致远处器官转移。在结直肠癌标本中，D-2HG水平升高，特别是与远处转移相关的标本，这支持了体外的观察结果，并暗示D-2HG在转移中的作用，转移是该病的主要死亡原因。
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.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
DOI：
10.1158/1055-9965.epi-15-0697
发表时间：
2016-01
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Liesenfeld DB;Botma A;Habermann N;Toth R;Weigel C;Popanda O;Klika KD;Potter JD;Lampe JW;Ulrich CM
通讯作者：
Ulrich CM
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A