Kondo Yutaka, Shen Lanlan, Cheng Alfred S, Ahmed Saira, Boumber Yanis, Charo Chantale, Yamochi Tadanori, Urano Takeshi, Furukawa Koichi, Kwabi-Addo Bernard, Gold David L, Sekido Yoshitaka, Huang Tim Hui-Ming, Issa Jean-Pierre J
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Nat Genet. 2008 Jun;40(6):741-50. doi: 10.1038/ng.159. Epub 2008 May 18.
Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation.
癌细胞中的表观遗传沉默由至少两种不同的组蛋白修饰介导，即基于多梳蛋白的组蛋白H3赖氨酸27三甲基化（H3K27triM）和H3K9二甲基化。DNA高甲基化与这些组蛋白修饰之间的关系尚未完全明确。与正常前列腺组织相比，利用染色质免疫沉淀微阵列（ChIP-chip）技术对前列腺癌细胞进行研究，我们发现高达5%的启动子（16%的CpG岛和84%的非CpG岛）富含H3K27triM。这些基因在前列腺癌中特异性沉默，且受影响的CpG岛显示出低水平的DNA甲基化。EZH2组蛋白甲基转移酶的下调单独或与组蛋白去乙酰化酶抑制协同作用时，可恢复H3K27triM靶基因的表达，而不影响启动子DNA甲基化，对因DNA高甲基化而沉默的基因表达也无影响。这些数据表明，EZH2介导的H3K27triM是癌症中肿瘤抑制基因沉默的一种机制，可能独立于启动子DNA甲基化。
