Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells (Retracted article. See vol. 141, pg. 1492, 2017)
Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells (Retracted article. See vol. 141, pg. 1492, 2017)
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DOI：
10.1002/ijc.23590
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发表时间：
2008-08-01
影响因子：
6.4
通讯作者：
Dahiya, Rajvir
中科院分区：
文献类型：
--
作者：
Kikuno, Nobuyuki;Shiina, Hiroaki;Dahiya, Rajvir
染料木黄酮是一种植物雌激素，据报道可抑制多种恶性肿瘤中的AKT信号通路。然而，染料木黄酮作用的分子机制尚不清楚。我们测试了染料木黄酮激活几个异常沉默的肿瘤抑制基因（TSGs）的表达的假设，这些基因具有非甲基化的启动子，如PTEN，CYLD，p53和FOX 03 a。我们在这里报告，染料木黄酮激活TSGs通过在前列腺癌细胞的启动子异染色质结构域的重塑，通过调节组蛋白H3-赖氨酸9（H3-K9）甲基化和脱乙酰化。染料木黄酮的活化涉及H3-K9在PTEN和CYLD启动子处的去甲基化和乙酰化，而H3-K9在p53和FOX 03 a启动子处的乙酰化通过降低内源性SIRT 1活性而发生。SIRT 1表达减少，SIRT 1从细胞核聚集在细胞质中。这些TSGs表达的增加也与前列腺癌细胞中磷酸化AKT和NF-κ B结合活性的减弱密切相关。这是第一份报告描述了一种新的表观遗传途径，该途径通过调节组蛋白H3-赖氨酸9（H3-K9）甲基化或基因启动子的脱乙酰化来激活TSGs，从而抑制AKT信号传导途径。这些发现加强了对染料木黄酮如何在前列腺癌中起化学保护作用的理解。(C)2008 Wiley-Liss，Inc.
Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOX03a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOX03a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-kappa B binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer. (C) 2008 Wiley-Liss, Inc.