Journal of Steroid Biochemistry & Molecular Biology, 2010, 120(4-5):164-71.

Long-term genistein treatment of MCF-7 cells decreases acetylated histone 3 expression and alters growth responses to mitogens and histone deacetylase inhibitors

Kiran Jawaid, Jennifer L. Nowers, et al

Division of Basic Medical Sciences, St George's University of London, Cranmer Terrace, London SW17 ORE, United Kingdom

Defects in epigenetic regulation of gene transcription play an important role in carcinogenesis of the breast and other tissues. The two most widely studied epigenetic changes are DNA methylation and acetylation of histone proteins and inhibition of these processes inhibits growth in breast cancer cell lines. These data coupled with the evidence that fetal and neonatal exposure to oestrogenic substances may lead to epigenetic changes that predispose or protect against the development of breast cancer in later life formed the basis for this study. Three histone deacetylases, valproic acid (VPA), trichostatin A (TCA) and apicidin dose-dependently inhibited basal growth in MCF-7 and MDA-MB-231 as well as the growth promoting effects of oestradiol (E(2)) and epidermal growth factor (EGF) in MCF-7 cells. The growth inhibitory responses to the DNA methyl transferase inhibitor, 5-aza-2'deoxycytidine (decitabine) were weak. HDACi's reduced the protein levels of pro-caspase 9 and cyclin D1, whereas decitabine had no effect. Long-term genistein treatment (LTGT) of MCF-7 cells markedly reduced the basal expression of acetylated histone 3 (H3) and the effects of HDACi's on increasing the levels of acetylated H3 protein. However, this was not correlated with a reduced expression of total H3 except after a high dose of VPA. LTGT inhibited growth of MCF-7 cells and the mitogenic responses to E(2) and EGF. The growth inhibitory responses to HDACI's in the presence of E(2) and EGF was significantly reduced in LTGT cells compared to control MCF-7 cells and there was evidence that LTGT maintained the protein levels of pro-caspase 9 in the presence of HDACi's. This study provides further evidence that oestrogenic substances can induce significant epigenetic changes to alter the dynamics of growth in breast cancer cell lines.

英国《激素生物化学和分子生物学杂志》，2010年6月

染料木黄酮对MCF-7 细胞的长期处理降低了乙酰化组蛋白 3 表达并且改变了对分裂素和组蛋白去乙酰化酶抑制剂的生长反应

凯兰 扎维德，詹妮弗  L 诺沃斯等

英国伦敦圣乔治大学基础医学部

缺陷在表观遗传调控基因转录时在乳腺和其他组织的癌变过程中发挥重要作用。观遗传变化的两个最广泛研究表是 DNA 甲基化和组蛋白乙酰化，并且对这些过程的抑制会抑制乳腺癌细胞的生长。这些数据加上证据表明，胎儿和新生儿暴露在雌激素物质中可能会导致表观遗传的变化，易患或防止在以后的生活中患乳腺癌的发展形成本研究的基础。三种组蛋白去乙酰化酶： 丙戊酸钠 (VPA)、 曲古霉素(TCA) 和 组蛋白去乙酰化酶抑制剂 剂量依赖性地抑制 了MCF-7 和 MDA-MB-231 的基本生长，以及在MCF-7 细胞中具有促生长效果的雌二醇 （E(2)) 和表皮生长因子 (EGF)。DNA 甲基转移酶抑制剂的生长抑制反应，5-氮杂-2' 脱氧胞苷 （地西他滨） 较弱。HDACi 降低了 pro-半胱氨酸蛋白酶 9 和细胞周期素 D1的 蛋白水平，而地西他滨没有效果。染料木黄酮对MCF-7 细胞的长期治疗 (LTGT)明显降低了乙酰化组蛋白 3 (H3) 的基础表达以及 HDACi 提高乙酰化 H3 蛋白水平的作用。然而，除了高剂量丙戊酸钠之外，这并不与总 H3表达减少相关。LTGT 抑制了MCF-7 细胞的生长以及E（2） 和表皮生长因子有丝分裂反应的生长。在E （2） 和表皮生长因子存在的情况下HDACI生长抑制的反应在 LTGT 细胞中相比于对照MCF-7 细胞明显减少。并且有证据表明当 HDACi存在时LTGT 可以维持对 pro-半胱氨酸蛋白酶9蛋白质水平。这项研究提供了进一步的证据，雌激素物质可以诱导重要的表观遗传变化，改变乳腺癌细胞的生长动力学。