Journal of Steroid Biochemistry & Molecular Biology, 2015, 152:62-75.

Genistein increases estrogen receptor beta expression in prostate  cancer via reducing its promoter methylation

Abeer M. Mahmoud, Mohamed M. Ali, et al

Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA; School of Public Health, University of Illinois at Chicago, Chicago, IL, USA; School of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA

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.

英国《类固醇生物化学与分子生物学杂志》，2015年8月

金雀异黄素通过减少启动子甲基化增加前列腺癌雌激素受体 β 的表达

阿比尔 M. 穆罕默德， 穆罕默德 M. 阿莱，等

美国伊利诺斯大学芝加哥分校病理学系; 伊利诺斯大学芝加哥分校公共卫生学院; 伊利诺斯大学芝加哥分校应用健康科学学院

金雀异黄素具有对前列腺癌（PCa）的保护作用，但是这种保护是否涉及雌激素受体（ER）β的依赖性机制尚待阐明。 ER-β在PCa中具有肿瘤抑制作用，其水平随着与ER-β启动子高甲基化相关的癌症进展而下降。 金雀异黄素被认为在癌症中具有去甲基化活性。 然而，金雀异黄素逆转PCa中ER-β启动子超甲基化的能力尚未得到研究。 另外，金雀异黄素对ER-β基因表达影响的研究存在很大的差异。 因此，我们试图探索金雀异黄素对ER-β启动子甲基化的影响，作为三种PCa细胞系LNCaP，LAPC-4和PC-3调节ER-β表达的机制。我们还研究了ER-β在金雀异黄素调节预防作用方面的影响。 我们的数据表明，生理范围（0.5-10μmol/ L）的金雀异黄素明显降低了ER-β启动子的甲基化，LNCaP和LAPC-4中的ER-β表达与PC-3细胞中ER-β的表达呈剂量依赖性增加，这些归因于PC-3细胞系中ER-β启动子甲基化的基础水平较低。在三种PCa细胞系中金雀异黄素诱导ER-β磷酸化，核易位和转录活性。使用特异性ER-β拮抗剂，金雀异黄素对LAPC-4和PC-3细胞增殖的抑制作用减弱。 总之，金雀异黄素和ER-β共同作用以预防PCa细胞增殖; 金雀异黄素通过减少启动子甲基化和ER-β来提高ER-β的水平，从而调节金雀异黄素的预防作用。