Wei Yongkun, Xia Weiya, Zhang Zhihong, Liu Jinsong, Wang Huamin, Adsay Nazmi V, Albarracin Constance, Yu Dihua, Abbruzzese James L, Mills Gordon B, Bast Robert C, Hortobagyi Gabriel N, Hung Mien-Chie
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Mol Carcinog. 2008 Sep;47(9):701-6. doi: 10.1002/mc.20413.
Methylation of lysine 27 on histone H3 (H3K27) by the EZH2 complex is an epigenetic mark that mediates gene silencing. EZH2 is overexpressed in many cancers and correlates with poor prognosis in both breast and prostate cancers. However, the status of H3K27 methylation and its clinical implication in cancer patients have not been reported. We thus examined trimethylation of H3K27 (H3K27me3) by immunohistochemistry and its association with clinical variables and prognosis in breast, ovarian, and pancreatic cancers. We found that H3K27me3 expression was significantly lower in breast, ovarian and pancreatic cancers than in normal tissues (62% in breast cancer vs. 88% in normal breast tissue, P = 0.001; 38.4% in ovarian cancer vs. 83.3% in normal ovarian tissue, P < 0.05; and 26% in pancreatic cancer vs. 89% in normal pancreatic tissue, P < 0.001). H3K27me3 expression showed significant prognostic impact in breast, ovarian and pancreatic cancers in univariate survival analyses. In all three cancer types, patients with low expression of H3K27me3 had significantly shorter overall survival time when compared with those with high H3K27me3 expression. In a multivariate model, H3K27me3 expression was an independent prognostic value for overall survival in all three cancer types. These results suggest that H3K27me3 expression is a prognostic indicator for clinical outcome in patients with breast, ovarian, and pancreatic cancers.
EZH2复合物对组蛋白H3上赖氨酸27位点（H3K27）的甲基化是一种介导基因沉默的表观遗传标记。EZH2在许多癌症中均有过表达，且与乳腺癌和前列腺癌的不良预后相关。然而，H3K27甲基化状态及其在癌症患者中的临床意义尚未见报道。因此，我们通过免疫组织化学检测了H3K27的三甲基化（H3K27me3），并研究了其与乳腺癌、卵巢癌和胰腺癌患者临床变量及预后的关系。我们发现，乳腺癌、卵巢癌和胰腺癌组织中H3K27me3的表达显著低于正常组织（乳腺癌中为62%，正常乳腺组织中为88%，P = 0.001；卵巢癌中为38.4%，正常卵巢组织中为83.3%，P < 0.05；胰腺癌中为26%，正常胰腺组织中为89%，P < 0.001）。单因素生存分析显示，H3K27me3表达对乳腺癌、卵巢癌和胰腺癌的预后有显著影响。在所有这三种癌症类型中，与H3K27me3高表达患者相比，H3K27me3低表达患者的总生存时间显著缩短。在多变量模型中，H3K27me3表达是所有这三种癌症类型总生存的独立预后指标。这些结果表明，H3K27me3表达是乳腺癌、卵巢癌和胰腺癌患者临床结局的预后指标。
