nature20121206-5

来自美国葛兰素史克公司的科学家证实EZH2甲基转移酶活性抑制剂GSK126能有效地抑制EZH2突变的DLBCL细胞系的增殖,并显著抑制EZH2突变的DLBCL异种嫁接瘤的生长。该研究表明EZH2活性的药理学抑制可能为EZH2突变淋巴瘤提供了有望的治疗方法。

-2012年12月6日《自然》

中文翻译


【题目】EZH2抑制是EZH2激活突变淋巴瘤的治疗策略

【译文】真核生物中,组蛋白的转录后修饰对于染色质结构和基因表达的调控至关重要。EZH2是多梳抑制复合物2(PRC2)的催化亚单位,并通过组蛋白H3在赖氨酸27位(H3K27)上的甲基化参与抑制基因表达过程。EZH2过表达与肿瘤发生和一些肿瘤的较差预后相关。此外,EZH2的催化性SET结构域内Y641和A677残基的体细胞杂合突变发生在弥漫大B细胞型淋巴瘤(DLBCL)和滤泡性淋巴瘤中。Y641残基是最常突变的残基,有高达22%的生发中心B细胞DLBCL和滤泡性淋巴瘤具有此位点上的突变。由于改变了突变的酶的底物参数,这些淋巴瘤增加了H3K27的三甲基化作用(H3K27me3)。然而,目前尚不清楚EZH2甲基化转移酶活性的特异性直接抑制是否在治疗EZH2突变的淋巴瘤中有效。本研究证实了GSK126(EZH2甲基转移酶活性的一种潜在的、高度选择性的S-腺苷蛋氨酸竞争性的小分子抑制剂)减少了总体H3K27me3水平,恢复了沉默的PRC2靶基因。 GSK126有效地抑制了EZH2突变的DLBCL细胞系的增殖,并显著抑制小鼠中EZH2突变的DLBCL异种嫁接瘤的生长。总之,这些数据证实了EZH2活性的药理学抑制可能为EZH2突变淋巴瘤提供了有前景的治疗方法。

英文原稿


[Title]: EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations

[Authors]:Michael T. McCabe,1 Heidi M. Ott,1 Gopinath Ganji,1 Susan Korenchuk,1 Christine Thompson,1 Glenn S. Van Aller,1 Yan Liu,1 Alan P. Graves,2 Anthony Della Pietra III,1 Elsie Diaz,2 Louis V. LaFrance,1 Mark Mellinger,1 Celine Duquenne,1 Xinrong Tian,1 Ryan G. Kruger,1 Charles F. McHugh,1 Martin Brandt,2 William H. Miller,1 Dashyant Dhanak,1 Sharad K. Verma,1 Peter J. Tummino1 & Caretha L. Creasy1

[Abstract]In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.

原文地址

http://www.nature.com/nature/journal/v492/n7427/full/nature11606.html

 

本站声明: 生物文库所有文章欢迎转载,所有文章未说明,均属于原创,转载均请注明出处。
本文链接: http://www.bioku.cn/201301/nature-ezh2-lymphoma-therapeutic-strategy/
版权所有: 生物文库 - 生物医学、生物技术核心期刊文摘

留言


5 − 四 =


沪ICP备12028140号
点击这里给我发消息   点击这里给我发消息