Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification
Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification
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DOI：
10.1158/0008-5472.can-07-2290
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发表时间：
2008-04-15
期刊：
影响因子：
11.2
通讯作者：
Dahiya, Rajvir
中科院分区：
文献类型：
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作者：
Majid, Shahana;Kikuno, Nobuyuki;Dahiya, Rajvir
染料木黄酮（4 '，5，7-三羟基黄酮）是大豆中含量最丰富的黄酮类化合物。染料木黄酮对各种癌细胞系的作用已被广泛研究，但确切的分子机制尚不清楚。我们在这里报告的表观遗传机制的染料木素对雄激素敏感（LNCaP）和雄激素不敏感（DuPro）的人前列腺癌细胞系的行动。Genistein诱导肿瘤抑制基因p21（WAF 1/CIP 1/KIP 1）和p16（INK 4a）的表达，同时细胞周期蛋白减少。Genistein处理后，LNCaP细胞出现G 0-G1期阻滞，DuPro细胞出现G2-M期阻滞。染料木黄酮还诱导DuPro细胞凋亡。DNA甲基化分析显示，在这两种细胞系中没有p21启动子甲基化。染料木黄酮对染色质重塑的影响以前没有报道。我们发现，染料木黄酮增加乙酰化的历史3，4，和H3/K4在p21和p16转录起始位点。此外，我们发现，金雀花碱处理还增加了在转录激活中起作用的历史乙酰转移酶的表达。这是第一份关于染料木素通过染色质重塑对前列腺癌中各种基因的表观遗传调控的报告。总而言之，我们的数据提供了新的见解的表观遗传机制的染料木黄酮的行动，可能有助于这种饮食的化学预防活性，并具有重要意义的表观遗传治疗。
Genistein (4',5,7-trihydroxyisoflavone) is the most abundant isoflavone found in the soybean. The effects of genistein on various cancer cell lines have been extensively studied but the precise molecular mechanisms are not known. We report here the epigenetic mechanism of the action of genistein on androgen-sensitive (LNCaP) and androgen-insensitive (DuPro) human prostate cancer cell lines. Genistein induced the expression of tumor suppressor genes p21 (WAF1/CIP1/KIP1) and p16 (INK4a) with a concomitant decrease in cyclins. There was a GO-G, cell cycle arrest in LNCaP cells and a G(2)-M arrest in DuPro cells after genistein treatment. Genistein also induced apoptosis in DuPro cells. DNA methylation analysis revealed the absence of p21 promoter methylation in both cell lines. The effect of genistein on chromatin remodeling has not been previously reported. We found that genistein increased acetylated histories 3, 4, and H3/K4 at the p21 and p16 transcription start sites. Furthermore, we found that genistem treatment also increased the expression of historic acetyl transferases that function in transcriptional activation. This is the first report on epigenetic regulation of various genes by genistein through chromatin remodeling in prostate cancer. Altogether, our data provide new insights into the epigenetic mechanism of the action of genistein that may contribute to the chemopreventive activity of this dietary isoflavone and have important implications for epigenetic therapy.