Genistein increases estrogen receptor beta expression in prostate cancer via reducing its promoter methylation.
Genistein increases estrogen receptor beta expression in prostate cancer via reducing its promoter methylation.
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DOI：
10.1016/j.jsbmb.2015.04.018
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Bosland MC
中科院分区：
文献类型：
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作者：
Mahmoud AM;Al-Alem U;Ali MM;Bosland MC
金雀异黄素对前列腺癌有保护作用，但这种保护作用是否涉及雌激素受体(ER)β依赖机制尚不清楚。ER-β在前列腺癌中具有肿瘤抑制作用，其水平随肿瘤进展而下降，这与ER-β启动子高甲基化有关。金雀异黄素已被认为在癌症中具有去甲基化活性。然而，金雀异黄素逆转前列腺癌ER-β启动子高甲基化的能力尚未被研究。此外，研究染料木素对ER-β基因表达的影响的研究也存在很大差异。因此，我们试图利用三种前列腺癌细胞株LNCaP、LAPC-4和PC-3来探讨染料木黄酮对ER-β启动子甲基化的影响，作为调控ER-β表达的机制。我们还研究了ER-β在金雀异黄素预防作用中的作用。结果表明，在生理浓度范围内(0.5~10µm o l/L)染料木黄酮显著降低ER-β启动子甲基化水平，相应剂量依赖性地增加ER-β在LNCaP和LAPC-4细胞中的表达，但在PC-3细胞中无此作用，这可能是由于PC-3细胞中ER-β启动子甲基化水平较低所致。金雀异黄素诱导三种前列腺癌细胞系ER-β的磷酸化、核转位和转录活性。特异性ER-β拮抗剂可减弱金雀异黄素对LAPC-4和PC-3细胞增殖的抑制作用。综上所述，金雀异黄素和ER-β共同抑制前列腺癌细胞的增殖；金雀异黄素通过减少其启动子甲基化来增加ER-β的水平，而ER-β则介导了金雀异黄素的预防作用。
Genistein has protective effects against prostate cancer (PCa) but whether this protection involves an estrogen receptor (ER) β dependent mechanism has yet to be elucidated. ER-β has a tumor suppressor role in PCa and its levels decline with cancer progression which was linked to ER-β promoter hypermethylation. Genistein has been suggested to have demethylating activities in cancer. However, the ability of genistein to reverse ER-β promoter hypermethylation in PCa has not been studied. In addition, there are great discrepancies among studies that examined the effect of genistein on ER-β gene expression. Therefore, we sought to explore effects of genistein on ER-β promoter methylation as a mechanism of modulating ER-β expression using three PCa cell lines, LNCaP, LAPC-4 and PC-3. We also examined the role of ER-β in mediating the preventive action of genistein. Our data demonstrated that genistein at physiological ranges (0.5–10 µmol/L) reduced ER-β promoter methylation significantly with corresponding dose-dependent increases in ER-β expression in LNCaP and LAPC-4 but not in PC-3 cells, which could be attributed to the low basal levels of ER-β promoter methylation in PC-3 cell line. Genistein induced phosphorylation, nuclear translocation and transcriptional activity of ER-β in all three PCa cell lines. Inhibitory effects of genistein on LAPC-4 and PC-3 cell proliferation were diminished using a specific ER-β antagonist. In conclusion, genistein and ER-β act together to prevent PCa cell proliferation; genistein increases ER-β levels via reducing its promoter methylation and ER-β, in turn, mediates the preventive action of genistein.