Glutathione-S-transferase pi 1(GSTP1) gene silencing in prostate cancer cells is reversed by the histone deacetylase inhibitor depsipeptide
Glutathione-S-transferase pi 1(GSTP1) gene silencing in prostate cancer cells is reversed by the histone deacetylase inhibitor depsipeptide
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DOI：
10.1016/j.bbrc.2011.08.007
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发表时间：
2011-09-09
影响因子：
3.1
通讯作者：
Ellinger, Joerg
中科院分区：
文献类型：
--
作者：
Hauptstock, Vera;Kuriakose, Sapuna;Ellinger, Joerg
表观遗传学机制导致的基因沉默在前列腺癌（PCA）中很常见。DNA超甲基化与组蛋白修饰之间的联系尚未完全了解。我们选择了GSTP 1基因，这是沉默的超甲基化，以分析组蛋白去乙酰化酶抑制剂缩酚酸肽对DNA甲基化和组蛋白修饰的GSTP 1启动子位点的影响。前列腺细胞系（PC-3，LNCaP和BPH-1）与缩肽处理;细胞凋亡（流式细胞仪分析），GSTP 1 mRNA水平（定量实时PCR），DNA超甲基化（甲基化特异性PCR），和组蛋白修饰（染色质免疫沉淀）进行了研究。Depsipeptide诱导PCA细胞凋亡，但不诱导细胞周期停滞。Depispeptide逆转DNA超甲基化和抑制性组蛋白修饰（H3 K9 me 2/3和H3 K27 me 2/3减少; H3 K18 Ac增加），从而诱导GSTP 1 mRNA再表达。成功的治疗需要DNA去甲基化和激活组蛋白修饰两者，以诱导表观遗传学沉默基因的完全基因表达，而缩肽满足这两个标准。(C)2011 Elsevier Inc. All rights reserved.
Gene silencing by epigenetic mechanisms is frequent in prostate cancer (PCA). The link between DNA hypermethylation and histone modifications is not completely understood. We chose the GSTP1 gene which is silenced by hypermethylation to analyze the effect of the histone deacetylase inhibitor depsipeptide on DNA methylation and histone modifications at the GSTP1 promoter site. Prostate cell lines (PC-3, LNCaP, and BPH-1) were treated with depsipeptide; apoptosis (FACS analysis), GSTP1 mRNA levels (quantitative real-time PCR), DNA hypermethylation (methylation-specific PCR), and histone modifications (chromatin immunoprecipitation) were studied. Depsipeptide induced apoptosis in PCA cells, but not a cell cycle arrest. Depispeptide reversed DNA hypermethylation and repressive histone modifications (reduction of H3K9me2/3 and H3K27me2/3; increase of H3K18Ac), thereby inducing GSTP1 mRNA re-expression. Successful therapy requires both, DNA demethylation and activating histone modifications, to induce complete gene expression of epigenetically silenced genes and depsipeptide fulfils both criteria. (C) 2011 Elsevier Inc. All rights reserved.