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’.
Highlights
The kinetics of IGFBP3 and G0S2 mRNA regulation were highly pronounced in RWPE-1 cells
We examined whether the co-repressor protein NCOR1 was differentially recruited to target genes that are known to regulate these anti-mitotic transcriptional programs
As a starting point to these questions the current study examined differential mRNA regulation of two vitamin D receptor (VDR) target genes in different prostate cell models
Summary
Non-malignant and malignant prostate cell lines display a range of anti-proliferative responses toward 1␣,25(OH)2D3. The mRNA was significantly reduced in PC-3 at multiple time points Together these data indicate that gene regulation by 1␣,25(OH)2D3 was most dynamic in cells that were most responsive to the anti-proliferative effects (RWPE-1 cells). Enhanced 1␣,25(OH)2D3-regulated NCOR1 recruitment was evident in 1␣,25(OH)2D3-recalcitrant PC-3 cells compared to 1␣,25(OH)2D3sensitive RWPE-1 at these regions examined This occurred rapidly on both genes in PC-3 cells within the first hour of exposure to 1␣,25(OH)2D3, compared to RWPE-1 cells, NCOR1 appeared to cycle off and be subsequently recruited back at later time points; at 24 h on the IGFBP3 response element and at 2 and 12 h on the TSS of G0S2 (data not shown). These findings suggest the underlying mechanisms of recruitment of NCOR1 in response to VDR activation differ significantly between the two cell types
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