Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
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DOI：
10.1016/j.molonc.2012.06.002
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发表时间：
2012-10-01
影响因子：
6.6
通讯作者：
Ringner, Markus
中科院分区：
文献类型：
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作者：
Holm, Karolina;Grabau, Dorthe;Ringner, Markus
多梳抑制复合物2（PRC2）及其核心成员果蝇zeste基因增强子同源物2（EZH2）介导表观遗传基因沉默标记：组蛋白3上赖氨酸27的三甲基化（H3K27me3）。H3K27me3是未分化细胞中参与发育调控的基因的染色质特征。在几种癌症类型中，如乳腺癌、前列腺癌、黑色素瘤和膀胱癌，已发现EZH2过表达。此外，过表达与高增殖性和侵袭性的乳腺癌和前列腺肿瘤类型相关。我们使用免疫组织化学方法在两个大型且特征明确的乳腺癌肿瘤数据集（包含400多个肿瘤）中分析了EZH2和H3K27me3的丰度。结果根据乳腺癌肿瘤的分子亚型（基底样、腔面A、腔面B、HER2富集和正常样）以及由临床标志物定义的亚型（三阴性、ER +/HER2 -/Ki67低、ER +/HER2 -/Ki67高和HER2 +）进行了分析，并通过蛋白质印迹在具有代表性的乳腺癌细胞系中进行了验证。我们发现所有亚型中EZH2和H3K27me3的表达均存在显著差异，EZH2在基底样、三阴性和HER2富集肿瘤中高表达，H3K27me3在腔面A、HER2富集和正常样肿瘤中高表达。有趣的是，这两种标志物呈负相关，特别是对于基底样和三阴性肿瘤。因此，EZH2的高表达与较差的远处无病生存率相关，而H3K27me3的高表达与较好的生存率相关。此外，在182个乳腺癌肿瘤中未发现有先前描述的影响Tyr641的EZH2突变。我们观察到EZH2表达增加并不一定与H3K27me3丰度增加相关，这支持了EZH2在乳腺癌中对靶基因的作用可能超出表观遗传沉默的观点。（c）2012欧洲生物化学学会联合会。由爱思唯尔出版集团出版。保留所有权利。
Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and Well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer. (c) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.