Epigenetic silencing of microRNA-218 via EZH2-mediated H3K27 trimethylation is involved in malignant transformation of HBE cells induced by cigarette smoke extract
Epigenetic silencing of microRNA-218 via EZH2-mediated H3K27 trimethylation is involved in malignant transformation of HBE cells induced by cigarette smoke extract
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EZH2介导的H3K27三甲基化导致的microRNA-218表观遗传沉默参与了香烟烟雾提取物诱导的HBE细胞的恶性转化
DOI：
10.1007/s00204-014-1435-z
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发表时间：
2016-02-01
影响因子：
6.1
通讯作者：
Xiang, Quanyong
中科院分区：
文献类型：
--
作者：
Wang, Bairu;Liu, Yi;Xiang, Quanyong
mirna的异常表达与人类肺癌的发病机制有关，其中大多数可归因于吸烟。然而，其作用机制仍不清楚。在这里，我们报道了在香烟烟雾提取物（CSE）诱导的人支气管上皮（HBE）细胞转化过程中，miR-218的表达降低，EZH2和H3K27me3的表达增加。通过siRNA或EZH2抑制剂3-deazaneplanocin A消耗EZH2，可以减轻cse诱导的miR-218水平的降低和H3K27me3（表观遗传学上控制基因转录）和BMI1（一种致癌基因）水平的升高。此外，ChIP实验表明，暴露于CSE的HBE细胞中，EZH2和H3K27me3在miR-218-1启动子处富集，表明EZH2通过组蛋白甲基化介导miR-218的表观遗传沉默。此外，miR-218直接靶向BMI1，通过miR-218消融转化HBE细胞中的癌症干细胞（CSCs）自我更新。在cse转化的HBE细胞中，过表达miR-218降低了Oct-4蛋白水平和CD133和CD44 mRNA水平（获得csc样特性的指标），过表达miR-218降低了转化的HBE细胞的恶性程度。因此，我们得出结论，通过ezh2介导的H3K27三甲基化对miR-218的表观遗传沉默参与了CSE诱导的csc样特性的获得和HBE细胞的恶性转化，从而促进了香烟烟雾的致癌作用。
Abnormal expression of miRNAs has been implicated in the pathogenesis of human lung cancers, most of which are attributable to cigarette smoke. The mechanisms of action, however, remain obscure. Here, we report that there are decreased expression of miR-218 and increased expression of EZH2 and H3K27me3 during cigarette smoke extract (CSE)-induced transformation of human bronchial epithelial (HBE) cells. Depletion of EZH2 by siRNA or by the EZH2 inhibitor, 3-deazaneplanocin A, attenuated CSE-induced decreases of miR-218 levels and increases of H3K27me3, which epigenetically controls gene transcription, and BMI1, an oncogene. Furthermore, ChIP assays demonstrated that EZH2 and H3K27me3 are enriched at the miR-218-1 promoter in HBE cells exposed to CSE, indicating that EZH2 mediates epigenetic silencing of miR-218 via histone methylation. In addition, miR-218 directly targeted BMI1, through which miR-218 ablates cancer stem cells (CSCs) self-renewal in transformed HBE cells. In CSE-transformed HBE cells, the protein level of Oct-4 and mRNA levels of CD133 and CD44, indicators of the acquisition of CSC-like properties, were reduced by over-expression of miR-218, and over-expression of miR-218 decreased the malignancy of transformed HBE cells. Thus, we conclude that epigenetic silencing of miR-218 via EZH2-mediated H3K27 trimethylation is involved in the acquisition of CSC-like properties and malignant transformation of HBE cells induced by CSE and thereby contributes to the carcinogenesis of cigarette smoke.