title: Epigenetic control of a VDR-governed feed-forward loop that regulates p21(waf1/cip1) expression and function in non-malignant prostate cells.
abstract: In non-malignant RWPE-1 prostate epithelial cells signaling by the nuclear receptor Vitamin D Receptor (VDR, NR1I1) induces cell cycle arrest through targets including CDKN1A (encodes p21((waf1/cip1))). VDR dynamically induced individual histone modification patterns at three VDR binding sites (R1, 2, 3) on the CDKN1A promoter. The magnitude of these modifications was specific to each phase of the cell cycle. For example, H3K9ac enrichment occurred rapidly only at R2, whereas parallel accumulation of H3K27me3 occurred at R1; these events were significantly enriched in G(1) and S phase cells, respectively. The epigenetic events appeared to allow VDR actions to combine with p53 to enhance p21((waf1/cip1)) activation further. In parallel, VDR binding to the MCM7 gene induced H3K9ac enrichment associated with rapid mRNA up-regulation to generate miR-106b and consequently regulate p21((waf1/cip1)) expression. We conclude that VDR binding site- and promoter-specific patterns of histone modifications combine with miRNA co-regulation to form a VDR-regulated feed-forward loop to control p21((waf1/cip1)) expression and cell cycle arrest. Dissection of this feed-forward loop in a non-malignant prostate cell system illuminates mechanisms of sensitivity and therefore possible resistance in prostate and other VDR responsive cancers.
authors.affiliation: Institute of Biomedical Research, University of Birmingham, Edgbaston B15 2TT, UK. Moray.Campbell@RoswellPark.org
authors.forename: James L
authors.initials: JL
authors.lastname: Thorne
authors.forename: Orla
authors.initials: O
authors.lastname: Maguire
authors.forename: Craig L
authors.initials: CL
authors.lastname: Doig
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Battaglia
authors.forename: Leah
authors.initials: L
authors.lastname: Fehr
authors.forename: Lara E
authors.initials: LE
authors.lastname: Sucheston
authors.forename: Merja
authors.initials: M
authors.lastname: Heinaniemi
authors.forename: Laura P
authors.initials: LP
authors.lastname: O'Neill
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Turner
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D035683:MicroRNAs; C543896:Mirn106 microRNA, mouse; D018167:Receptors, Calcitriol; D002117:Calcitriol