BMC Cancer, 2012, 12(1):1-11.

Genistein cooperates with the histone deacetylase inhibitor vorinostat to induce cell death in prostate cancer cells

Cornel J Phillip, Christopher K Giardina, Birdal Bilir, et al

Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaUSA; et al

BACKGROUND:

Among American men, prostate cancer is the most common, non-cutaneous malignancy that accounted for an estimated 241,000 new cases and 34,000 deaths in 2011. Previous studies have suggested that Wnt pathway inhibitory genes are silenced by CpG hypermethylation, and other studies have suggested that genistein can demethylate hypermethylated DNA. Genistein is a soy isoflavone with diverse effects on cellular proliferation, survival, and gene expression that suggest it could be a potential therapeutic agent for prostate cancer. We undertook the present study to investigate the effects of genistein on the epigenome of prostate cancer cells and to discover novel combination approaches of other compounds with genistein that might be of translational utility. Here, we have investigated the effects of genistein on several prostate cancer cell lines, including the ARCaP-E/ARCaP-M model of the epithelial to mesenchymal transition (EMT), to analyze effects on their epigenetic state. In addition, we investigated the effects of combined treatment of genistein with the histone deacetylase inhibitor vorinostat on survival in prostate cancer cells.

METHODS:

Using whole genome expression profiling and whole genome methylation profiling, we have determined the genome-wide differences in genetic and epigenetic responses to genistein in prostate cancer cells before and after undergoing the EMT. Also, cells were treated with genistein, vorinostat, and combination treatment, where cell death and cell proliferation was determined.

RESULTS:

Contrary to earlier reports, genistein did not have an effect on CpG methylation at 20 μM, but it did affect histone H3K9 acetylation and induced increased expression of histone acetyltransferase 1 (HAT1). In addition, genistein also had differential effects on survival and cooperated with the histone deacteylase inhibitor vorinostat to induce cell death and inhibit proliferation.

CONCLUSION:

Our results suggest that there are a number of pathways that are affected with genistein and vorinostat treatment such as Wnt, TNF, G2/M DNA damage checkpoint, and androgen signaling pathways. In addition, genistein cooperates with vorinostat to induce cell death in prostate cancer cell lines with a greater effect on early stage prostate cancer.

英国《BMC癌症》，2012年4月

在前列腺癌细胞中金雀异黄素与组蛋白去乙酰化酶抑制剂伏立诺他 共同诱导细胞死亡

柯奈尔 J 菲利普，克里斯托弗 K 加尔迪纳，达勒 皮列耳，等

美国亚特兰大埃默里医科大学病理教研室和实验室等

背景︰

在美国男性中，前列腺癌是最常见、 非上皮性的恶性肿瘤，在 2011 年估计有 241,000 例新病例和 34,000 人死亡。先前的研究表明 Wnt 通路抑制基因的声音被CpG 甲基化静默，并且其他的研究表明，金雀异黄素可以使高甲基化的DNA去甲基化。金雀异黄素是一种对细胞的增殖、 存活和基因的表达具有不同作用的大豆异黄酮，表明它可能是一种治疗前列腺癌的潜在药物。我们进行了本研究来调查金雀异黄素对前列腺癌细胞表观基因组的影响，发现将其他化合物与金雀异黄素相结合的新型方法可能有用。在这里，我们研究了金雀异黄素对几种前列腺癌细胞，包括上皮间质转换 (EMT) 的 ARCaP-E/ARCaP -M模型，分析对其表观遗传状态的影响。此外，我们研究了组蛋白去乙酰化酶抑制剂伏立诺他与金雀异黄素的联合治疗对前列腺癌细胞存活率的影响。

方法︰

利用全基因组表达谱和全基因组甲基化谱，我们测试了前列腺癌细胞中响应金雀异黄素的遗传和表观遗传在经历 EMT之前和之后的全基因组差异。此外，用金雀异黄素、伏立诺他和组合疗法治疗细胞，测定细胞的死亡和细胞增殖。

结果︰

根据先前的报道， 20μM的金雀异黄素对 CpG 甲基化没有影响，但它却影响了 H3K9 组蛋白乙酰化并诱导了组蛋白乙酰转移酶 1 (HAT1)的 表达增加。此外，金雀异黄素对生存率有差别性影响并且与组蛋白 脱乙酰基酶抑制剂伏立诺他联合诱导细胞凋亡和抑制增殖。

结论︰