title: Epigenetic distortion to VDR transcriptional regulation in prostate cancer cells.
abstract: The current study aimed to examine the gene specific mechanisms by which the actions of the vitamin D receptor (VDR) are distorted in prostate cancer. Transcriptional responses toward the VDR ligand, 1α,25(OH)2D3, were examined in non-malignant prostate epithelial cells (RWPE-1) and compared to the 1α,25(OH)2D3-recalcitrant prostate cancer cells (PC-3). Time resolved transcriptional studies for two VDR target genes revealed selective attenuation and repression of VDR transcriptional responses in PC-3 cells. For example, responses in PC-3 cells revealed suppressed responsiveness of IGFBP3 and G0S2. Furthermore, Chromatin Immunoprecipitation (ChIP) assays revealed that suppressed transcriptional responses in PC-3 cells of IGFBP3 and G0S2 were associated with selective VDR-induced NCOR1 enrichment at VDR-binding regions on target-gene promoter regions. We propose that VDR inappropriately recruits co-repressors in prostate cancer cells. Subsequent direct and indirect mechanisms may induce local DNA methylation and stable transcriptional silencing. Thus a transient epigenetic process mediated by co-repressor binding, namely, the control of H3K9 acetylation, is distorted to favor a more stable epigenetic event, namely DNA methylation. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Prashant K
authors.initials: PK
authors.lastname: Singh
authors.forename: Craig L
authors.initials: CL
authors.lastname: Doig
authors.forename: Vineet K
authors.initials: VK
authors.lastname: Dhiman
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Turner
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Smiraglia
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
mesh_terms: D002117:Calcitriol / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human; D002117:Calcitriol