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) 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.
Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA. Electronic address: amahmo4@uic.edu.
Abeer M
AM
Mahmoud
School of Public Health, University of Illinois at Chicago, Chicago, IL, USA.
Umaima
U
Al-Alem
School of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA.
Mohamed M
MM
Ali
Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
Maarten C
MC
Bosland
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic / Q000187:drug effects
C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; D047629:Estrogen Receptor beta; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D019833:Genistein
Estrogen receptor β; Genistein; Promoter methylation; Prostate cancer