Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 136, Issue -, Pages 258-263Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2012.10.002
Keywords
NCOR1; Prostate cancer; Epigenetics; VDR
Funding
- NucSys, a European Community FP6 - Marie Curie Research Training Network
- Biotechnology and Biological Sciences Research Council
- National Institute of Health [R01 CA095367-06, 2R01-CA-095045-06]
- NCI Cancer Center [CA016056]
- Alliance Foundation of Roswell Park Cancer Institute
- Cancer Research UK [C1015/A9077]
- Biotechnology and Biological Sciences Research Council [BB/D523651/1] Funding Source: researchfish
- BBSRC [BB/D523651/1] Funding Source: UKRI
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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, 1 alpha,25(OH)(2)D-3, were examined in non-malignant prostate epithelial cells (RWPE-1) and compared to the 1 alpha,25(OH)(2)D-3-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'. (c) 2012 Elsevier Ltd. All rights reserved.
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