Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells
Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells
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DOI：
10.1038/onc.2009.140
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发表时间：
2009-07-01
期刊：
影响因子：
8
通讯作者：
Hibi, T.
中科院分区：
文献类型：
--
作者：
Saito, Y.;Suzuki, H.;Hibi, T.
使用DNA甲基化抑制剂和组蛋白去乙酰化酶（HDAC）抑制剂的表观遗传疗法在治疗人类恶性肿瘤方面具有临床前景。为了研究microRNAs （miRNAs）在胃癌表观遗传治疗中的作用，我们分析了5-aza-2'-脱氧胞苷（5-Aza-CdR）和4-苯基丁酸（PBA）处理的人胃癌细胞中miRNA的表达谱。miRNA微阵列分析显示，胃癌细胞中被5-Aza-CdR和PBA激活的miRNA大部分位于19号染色体上的Alu重复序列。染色质修饰分析表明，DNA去甲基化和HDAC抑制Alu重复序列通过RNA聚合酶II激活沉默的miR-512-5p。此外，通过表观遗传处理激活miR-512-5p可诱导Mcl-1的抑制，导致胃癌细胞凋亡。这些结果表明，Alu重复序列的染色质重塑在调节miRNA表达中起着关键作用，并且表观遗传激活沉默的Alu相关miRNA可能是胃癌的一种新的治疗方法。中华肿瘤杂志（2009）28,2738-2744；doi: 10.1038 / onc.2009.140;2009年6月8日在线发布
Epigenetic therapy using DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors has clinical promise for the treatment of human malignancies. To investigate roles of microRNAs (miRNAs) on epigenetic therapy of gastric cancer, the miRNA expression profile was analysed in human gastric cancer cells treated with 5-aza-2'-deoxycytidine (5-Aza-CdR) and 4-phenylbutyric acid (PBA). miRNA microarray analysis shows that most of miRNAs activated by 5-Aza-CdR and PBA in gastric cancer cells are located at Alu repeats on chromosome 19. Analyses of chromatin modification show that DNA demethylation and HDAC inhibition at Alu repeats activates silenced miR-512-5p by RNA polymerase II. In addition, activation of miR-512-5p by epigenetic treatment induces suppression of Mcl-1, resulting in apoptosis of gastric cancer cells. These results suggest that chromatin remodeling at Alu repeats plays critical roles in the regulation of miRNA expression and that epigenetic activation of silenced Alu-associated miRNAs could be a novel therapeutic approach for gastric cancer. Oncogene (2009) 28, 2738-2744; doi:10.1038/onc.2009.140; published online 8 June 2009