State Key Laboratory for Liver Research and Department of Pathology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.
Hepatology. 2012 Aug;56(2):622-31. doi: 10.1002/hep.25679. Epub 2012 Jun 11.
Epigenetic alterations and microRNA (miRNA) deregulation are common in hepatocellular carcinoma (HCC). The histone H3 lysine 27 (H3K27) tri-methylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human cancers. In this study we aimed to delineate the implications of EZH2 up-regulation in miRNA deregulation and HCC metastasis. Expressions of a total of 90 epigenetic regulators were first determined in 38 pairs of primary HCCs and their corresponding nontumorous livers. We identified EZH2 and its associated polycomb repressive complex 2 (PRC2) as one of the most significantly deregulated epigenetic regulators in primary HCC samples. Up-regulation of EZH2 was next confirmed in 69.5% (41/59) of primary HCCs. Clinicopathologically, EZH2 up-regulation was associated with HCC progression and multiple HCC metastatic features, including venous invasion (P = 0.043), direct liver invasion (P = 0.014), and absence of tumor encapsulation (P = 0.043). We further demonstrated that knockdown of EZH2 in HCC cell lines reduced the global levels of tri-methylated H3K27, and suppressed HCC motility in vitro and pulmonary metastasis in a nude mouse model. By interrogating the miRNA expression profile in EZH2-knockdown cell lines and primary HCC samples, we identified a subset of miRNA that was epigenetically suppressed by EZH2 in human HCC. These included well-characterized tumor-suppressor miRNAs, such as miR-139-5p, miR-125b, miR-101, let-7c, and miR-200b. Pathway enrichment analysis revealed a common regulatory role of these EZH2-silenced miRNAs in modulating cell motility and metastasis-related pathways. Our findings suggest that EZH2 exerts its prometastatic function by way of epigenetic silencing of multiple tumor suppressor miRNAs.
Our study demonstrated that EZH2 epigenetically silenced multiple miRNAs that negatively regulate HCC metastasis.
表观遗传学改变和 microRNA（miRNA）失调在肝细胞癌（HCC）中很常见。组蛋白 H3 赖氨酸 27（H3K27）三甲基化酶，增强子的锌指蛋白 2（EZH2）介导基因表达的表观遗传沉默，并且在人类癌症中经常上调。在这项研究中，我们旨在描述 EZH2 上调在 miRNA 失调和 HCC 转移中的意义。首先在 38 对原发性 HCC 及其相应的非肿瘤性肝脏中确定了总共 90 种表观遗传调节剂的表达。我们确定 EZH2 及其相关的多梳抑制复合物 2（PRC2）是原发性 HCC 样本中最显着失调的表观遗传调节剂之一。EZH2 的上调在 69.5％（41/59）的原发性 HCC 中得到了进一步证实。临床病理分析表明，EZH2 的上调与 HCC 进展和多个 HCC 转移特征有关，包括静脉侵犯（P = 0.043），直接肝侵犯（P = 0.014）和肿瘤无包膜（P = 0.043）。我们进一步证明，在 HCC 细胞系中敲低 EZH2 降低了全局三甲基化 H3K27 水平，并在体外抑制 HCC 运动和裸鼠模型中的肺转移。通过在 EZH2 敲低细胞系和原发性 HCC 样本中检测 miRNA 表达谱，我们鉴定出一组由 EZH2 在人 HCC 中表观遗传抑制的 miRNA。其中包括经过充分研究的肿瘤抑制 miRNA，例如 miR-139-5p、miR-125b、miR-101、let-7c 和 miR-200b。途径富集分析显示这些被 EZH2 沉默的 miRNA 共同调节细胞运动和转移相关途径。我们的研究结果表明，EZH2 通过表观遗传沉默多个肿瘤抑制 miRNA 发挥其促转移功能。
我们的研究表明，EZH2 表观遗传沉默多个 miRNA，这些 miRNA 负调节 HCC 转移。
