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

Genistein has protective effects against prostate cancer (PCa) but whether this protection involves an estrogen receptor (ER) beta dependent mechanism has yet to be elucidated. ER-beta has a tumor suppressor role in PCa and its levels decline with cancer progression which was linked to ER-beta promoter hypermethylation. Genistein has been suggested to have demethylating activities in cancer. However, the ability of genistein-to reverse ER-beta promoter hypermethylation in PCa has not been studied. In addition, there are great discrepancies among studies that examined the effect of genistein on ER-beta gene expression. Therefore, we sought to explore effects of genistein on ER-beta promoter methylation as a mechanism of modulating ER-beta expression using three PCa cell lines, LNCaP, LAPC-4 and PC-3. We also examined the role of ER-beta in mediating the preventive action of genistein. Our data demonstrated that genistein at physiological ranges (0.5-10 mu mol/L) reduced ER-beta promoter methylation significantly with corresponding dose-dependent increases in ER-beta expression in LNCaP and LAPC-4 but not in PC-3 cells, which could be attributed to the low basal levels of ER-beta promoter methylation in PC-3 cell line. Genistein induced phosphorylation, nuclear translocation and transcriptional activity of ER-beta in all three PCa cell lines. Inhibitory effects of genistein on LAPC-4 and PC-3 cell proliferation were diminished using a specific ER-beta antagonist. In conclusion, genistein and ER-beta act together to prevent PCa cell proliferation; genistein increases ER-beta levels via reducing its promoter methylation and ER-beta, in turn, mediates the preventive action of genistein. (C) 2015 Elsevier Ltd. All rights reserved.