Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns
| Autor: | Craig L. Doig, Michelle Sobolewski, Sebastiano Battaglia, Christopher McCabe, Vineet K. Dhiman, Bryan M. Turner, Laura P. O'Neill, Moray J. Campbell, Dominic J. Smiraglia, James L. Thorne, Orla Maguire, Prashant Singh |
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| Rok vydání: | 2012 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male Chromatin Immunoprecipitation Cancer Research Original Manuscript Apoptosis Biology Real-Time Polymerase Chain Reaction Calcitriol receptor Epigenesis Genetic Calcitriol Humans Nuclear Receptor Co-Repressor 1 RNA Messenger Epigenetics Promoter Regions Genetic Cells Cultured Cell Proliferation Transrepression Regulation of gene expression Bone Density Conservation Agents Reverse Transcriptase Polymerase Chain Reaction Prostate Prostatic Neoplasms General Medicine DNA Methylation Gene Expression Regulation Neoplastic Histone Drug Resistance Neoplasm Histone methyltransferase DNA methylation Cancer research biology.protein Receptors Calcitriol Corepressor Signal Transduction |
| Zdroj: | Carcinogenesis. 34:248-256 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgs331 |
| Popis: | The current study investigated transcriptional distortion in prostate cancer cells using the vitamin D receptor (VDR) as a tool to examine how epigenetic events driven by corepressor binding and CpG methylation lead to aberrant gene expression. These relationships were investigated in the non-malignant RWPE-1 cells that were 1α,25(OH)(2)D(3) responsive (RWPE-1) and malignant cell lines that were 1α,25(OH)(2)D(3) partially responsive (RWPE-2) and resistant (PC-3). These studies revealed that selective attenuation and repression of VDR transcriptional responses in the cancer cell lines reflected their loss of antiproliferative sensitivity. This was evident in VDR target genes including VDR, CDKN1A (encodes p21( (waf1/cip1) )) and GADD45A; NCOR1 knockdown alleviated this malignant transrepression. ChIP assays in RWPE-1 and PC-3 cells revealed that transrepression of CDKN1A was associated with increased NCOR1 enrichment in response to 1α,25(OH)(2)D(3) treatment. These findings supported the concept that retained and increased NCOR1 binding, associated with loss of H3K9ac and increased H3K9me2, may act as a beacon for the initiation and recruitment of DNA methylation. Overexpressed histone methyltransferases (KMTs) were detectable in a wide panel of prostate cancer cell lines compared with RWPE-1 and suggested that generation of H3K9me2 states would be favored. Cotreatment of cells with the KMT inhibitor, chaetocin, increased 1α,25(OH)(2)D(3)-mediated induction of CDKN1A expression supporting a role for this event to disrupt CDKN1A regulation. Parallel surveys in PC-3 cells of CpG methylation around the VDR binding regions on CDKN1A revealed altered basal and VDR-regulated DNA methylation patterns that overlapped with VDR-induced recruitment of NCOR1 and gene transrepression. Taken together, these findings suggest that sustained corepressor interactions with nuclear-resident transcription factors may inappropriately transform transient-repressive histone states into more stable and repressive DNA methylation events. |
| Databáze: | OpenAIRE |
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