EZH2 Promotes Cholangiocarcinoma Development and Progression through Histone Methylation and microRNA-Mediated Down-Regulation of Tumor Suppressor Genes.
EZH2 Promotes Cholangiocarcinoma Development and Progression through Histone Methylation and microRNA-Mediated Down-Regulation of Tumor Suppressor Genes.
复制标题
DOI：
10.1016/j.ajpath.2022.08.008
复制
发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Jinqiang Zhang;Weina Chen;Wenbo Ma;Chang Han;K. Song;Hyunjoo Kwon;Tong Wu
中科院分区：
文献类型：
--
作者：
Jinqiang Zhang;Weina Chen;Wenbo Ma;Chang Han;K. Song;Hyunjoo Kwon;Tong Wu
胆管癌（CCA）是胆管系统的高度恶性癌症。尽管研究表明 Zeste 同源物 2 (EZH2) 增强子与 CCA 生长有关，但 EZH2 在 CCA 发育中的作用尚未得到研究，并且 EZH2 调节 CCA 中基因表达的机制仍有待进一步明确。目前的研究使用了通过尾静脉水动力注射Notch1胞内结构域和肉豆蔻酰化-AKT质粒诱导的CCA小鼠模型。肝脏特异性 EZH2 敲除的小鼠表现出 CCA 发育减少。在异种移植模型中，EZH2 敲除显着降低了 CCA 进展。 EZH2 抑制剂 GSK126 的给药可降低小鼠 CCA 肿瘤负荷。因此，EZH2 缺失或抑制降低了 CCA 细胞的生长和集落形成能力。高通量数据分析确定了一组 12 个肿瘤抑制基因作为 CCA 中 EZH2 的靶标。实验结果表明，EZH2可能通过基因虱子中组蛋白H3（H3K27）上赖氨酸27的甲基化以及通过调节特定miRNA来下调这些肿瘤抑制基因。高迁移率组框 1 可促进 EZH2 的甲基转移酶活性，这与 CCA 细胞生长的调节有关。研究表明，EZH2 通过一个涉及肿瘤抑制基因、miRNA 和高迁移率族蛋白 1 的复杂调控网络促进 CCA 的发生和进展，这支持将 EZH2 靶向作为 CCA 治疗的潜在有效策略。
Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tree. Although studies have implicated enhancer of Zeste homolog 2 (EZH2) in CCA growth, the role of EZH2 in CCA development has not been investigated, and the mechanism for EZH2-regulated gene expression in CCA remains to be further defined. The current study used a mouse model of CCA induced by hydrodynamic tail vein injection of Notch1 intracellular domain and myristoylated-AKT plasmids. Mice with liver-specific EZH2 knockout displayed reduced CCA development. In a xenograft model, EZH2 knockdown significantly decreased CCA progression. Administration of the EZH2 inhibitor GSK126 decreased CCA tumor burden in mice. Accordingly, EZH2 depletion or inhibition reduced the growth and colony formation capability of CCA cells. Analysis of high-throughput data identified a set of 12 tumor-inhibiting genes as targets of EZH2 in CCA. The experimental results suggest that EZH2 may down-regulate these tumor-inhibiting genes through methylation of lysine 27 on histone H3 (H3K27) in the gene louses and through regulation of specific miRNAs. High mobility group box 1 was shown to facilitate the methyltransferase activity of EZH2, which is implicated in the regulation of CCA cell growth. The study shows that EZH2 promotes CCA development and progression through a complicated regulatory network involving tumor-inhibiting genes, miRNAs, and high mobility group box 1, which support targeting EZH2 as a potentially effective strategy for CCA treatment.