Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells.
Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells.
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DOI：
10.1186/1868-7083-3-3
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发表时间：
2011
影响因子：
5.7
通讯作者：
Ho E
中科院分区：
文献类型：
--
作者：
Hsu A;Wong CP;Yu Z;Williams DE;Dashwood RH;Ho E
萝卜硫素（SFN），一种来自十字花科蔬菜的异硫氰酸酯，在前列腺癌细胞中诱导有效的抗增殖作用。可能有助于SFN的抗增殖作用的一种机制是调节表观遗传标记，例如抑制组蛋白脱乙酰酶（HDAC）酶。然而，SFN对其他常见的表观遗传标记（如DNA甲基化）的影响尚未得到充分研究。细胞周期蛋白D2（细胞周期的主要调节因子）的启动子超甲基化与前列腺癌进展相关，并且细胞周期蛋白D2表达的恢复对LnCap前列腺癌细胞发挥抗增殖作用。我们的研究旨在探讨SFN对LnCap细胞中cyclin D2基因启动子DNA甲基化状态的影响，以及启动子甲基化的改变如何影响cyclin D2基因的表达。我们发现SFN显著降低了DNA甲基转移酶（DNMTs）的表达，尤其是DNMT 1和DNMT 3b。此外，SFN显着降低甲基化的细胞周期蛋白D2启动子区域含有c-Myc和多个Sp1结合位点。细胞周期蛋白D2启动子甲基化的减少对应于细胞周期蛋白D2转录水平的增加，这表明SFN可能通过影响表观遗传途径来解除甲基化沉默的细胞周期蛋白D2的抑制。我们的研究结果表明，SFN表观遗传调节细胞周期蛋白D2的表达的能力，并提供新的见解的机制，SFN可以调节基因表达作为前列腺癌的化学预防剂。
Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, induces potent anti-proliferative effects in prostate cancer cells. One mechanism that may contribute to the anti-proliferative effects of SFN is the modulation of epigenetic marks, such as inhibition of histone deacetylase (HDAC) enzymes. However, the effects of SFN on other common epigenetic marks such as DNA methylation are understudied. Promoter hyper-methylation of cyclin D2, a major regulator of cell cycle, is correlated with prostate cancer progression, and restoration of cyclin D2 expression exerts anti-proliferative effects on LnCap prostate cancer cells. Our study aimed to investigate the effects of SFN on DNA methylation status of cyclin D2 promoter, and how alteration in promoter methylation impacts cyclin D2 gene expression in LnCap cells. We found that SFN significantly decreased the expression of DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3b. Furthermore, SFN significantly decreased methylation in cyclin D2 promoter regions containing c-Myc and multiple Sp1 binding sites. Reduced methlyation of cyclin D2 promoter corresponded to an increase in cyclin D2 transcript levels, suggesting that SFN may de-repress methylation-silenced cyclin D2 by impacting epigenetic pathways. Our results demonstrated the ability of SFN to epigenetically modulate cyclin D2 expression, and provide novel insights into the mechanisms by which SFN may regulate gene expression as a prostate cancer chemopreventive agent.