神經(jīng)膠質(zhì)瘤和白血病是惡性程度最高的人類腫瘤之一,，已對(duì)人類的生存造成極大威脅,。復(fù)旦大學(xué)生物醫(yī)學(xué)研究院博士研究生徐薇和楊輝，在該院分子細(xì)胞生物學(xué)研究室團(tuán)隊(duì)專家熊躍,、管坤良和趙世民3位教授指導(dǎo)下,，經(jīng)潛心研究，終于發(fā)現(xiàn)一種名叫“2HG”的人體代謝物誘發(fā)神經(jīng)膠質(zhì)瘤和白血病的作用機(jī)制,，這一新突破已于1月18日作為封面文章發(fā)表在腫瘤研究的國際頂級(jí)期刊《癌細(xì)胞》(Cancer Cell)上,。
課題領(lǐng)銜專家趙世民介紹，代謝是生命運(yùn)轉(zhuǎn)的基本過程,。人體攝入的葡萄糖,，在正常的情況下應(yīng)該在體內(nèi)被轉(zhuǎn)化的能量，通過二氧化碳的方式排出,，如果代謝不平衡,，多余的葡萄糖從尿液里面排出，就形成糖尿病,。腫瘤也是由于代謝不平衡產(chǎn)生的疾病,。
在人體的每一個(gè)代謝步驟中，都需要酶的作用,。此前的研究顯示,，一種異檸檬酸脫氫酶的基因變化，會(huì)產(chǎn)生一種名叫2HG的代謝物,。當(dāng)這種代謝垃圾積累到一定程度,，就會(huì)引發(fā)代謝問題，促進(jìn)正常細(xì)胞向癌細(xì)胞的轉(zhuǎn)化,。但2HG致癌的作用機(jī)制卻是一個(gè)謎團(tuán),，揭開這個(gè)謎團(tuán)對(duì)于癌癥、尤其是神經(jīng)膠質(zhì)瘤和白血病的發(fā)生及治療具有重要作用,。
趙世民教授（中）和他的研究團(tuán)隊(duì)成員徐薇（右2）,、楊輝（左2）等在實(shí)驗(yàn)室
課題組在研究中發(fā)現(xiàn)，2HG的累積可以直接抑制人體內(nèi)可控制多種細(xì)胞功能的生物酶,。這種雙加氧酶的活力降低后,，會(huì)改變細(xì)胞的增殖和生長方式,，進(jìn)而誘發(fā)腫瘤。人細(xì)胞內(nèi)的組蛋白甲基化水平高低是由組蛋白去甲基化酶的活力來控制,，控制得好,，人不會(huì)罹患癌癥，反之,，易患癌癥,。
《癌細(xì)胞》期刊表示，復(fù)旦大學(xué)生物醫(yī)學(xué)研究院研究團(tuán)隊(duì)這一研究成果的重要性在于發(fā)現(xiàn)了以人體內(nèi)“代謝物”為核心,、眾多雙加氧酶參與,、控制癌細(xì)胞發(fā)生和惡變的新途徑。這一發(fā)現(xiàn)可能對(duì)尋找新的神經(jīng)膠質(zhì)瘤治療靶點(diǎn)有積極的作用,。
據(jù)專家介紹,，神經(jīng)膠質(zhì)瘤治療沒有特效藥，以手術(shù)治療為主,，這一研究為包括神經(jīng)膠質(zhì)瘤在內(nèi)的多種人類腫瘤的藥物治療提供了新的靶點(diǎn)與干預(yù)方向,。（生物谷Bioon.com）
生物谷推薦原文出處：
Cancer Cell doi:10.1016/j.ccr.2010.12.014
Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
Wei Xu, Hui Yang, Ying Liu, Ying Yang, Ping Wang, Se-Hee Kim, Shinsuke Ito, Chen Yang, Pu Wang, Meng-Tao Xiao, Li-xia Liu, Wen-qing Jiang, Jing Liu, Jin-ye Zhang, Bin Wang, Stephen Frye, Yi Zhang, Yan-hui Xu, Qun-ying Lei, Kun-Liang Guan, Shi-min Zhao, Yue Xiong
Highlights
2-HG is a weak competitive inhibitor of α-KG-dependent dioxygenases
2-HG inhibits histone demethylases and TET 5-metyhlcytsine hydroxylases
Mutant IDH1 and 2-HG inhibits multiple α-KG-dependent dioxygenases
Mutant IDH1 and 2-HG alters genome-wide histone and DNA methylation
Summary
IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.
