摘要: 来自复旦大学生物医学研究院,北卡罗来纳大学教堂山分校(University of North Carolina at Chapel Hill)的研究人员发现了恶性程度最高的患神经胶质瘤和白血病是一种名叫“2HG”的代谢物诱发,从而成功破解人体代谢废物2HG致癌之谜。这一研究成果公布在Cell旗下的肿瘤研究国际顶级期刊《Cancer Cell》杂志(影响因子为:25.288),并被封面文章推荐给读者。
生物通报道:来自复旦大学生物医学研究院,北卡罗来纳大学教堂山分校(University of North Carolina at Chapel Hill)的研究人员发现了恶性程度最高的患神经胶质瘤和白血病是一种名叫“2HG”的代谢物诱发,从而成功破解人体代谢废物2HG致癌之谜。这一研究成果公布在Cell旗下的肿瘤研究国际顶级期刊《Cancer Cell》杂志(影响因子为:25.288),并被作为封面文章推荐给读者。
Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases 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.