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Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1α,25-dihydroxyvitamin D₃

Malinen, Marjo, Saramäki, Anna, Ropponen, Antti, Degenhardt, Tatjana, Väisänen, Sami, Carlberg, Carsten
Nucleic acids research 2008 v.36 no.1 pp. 121-132
RNA, calcitriol receptors, chromatin, cyclin-dependent kinase, epithelial cells, gene expression, genes, histone deacetylase, humans, mammary glands, multiprotein complexes, precipitin tests, transcription (genetics)
The anti-proliferative effects of histone deacetylase (HDAC) inhibitors and 1α,25-dihydroxyvitamin D₃ [1α,25(OH)₂D₃] converge via the interaction of un-liganded vitamin D receptor (VDR) with co-repressors recruiting multiprotein complexes containing HDACs and via the induction of cyclin-dependent kinase inhibitor (CDKI) genes of the INK4 and Cip/Kip family. We investigated the effects of the HDAC inhibitor Trichostatin A (TSA) and 1α,25(OH)₂D₃ on the proliferation and CDKI gene expression in malignant and non-malignant mammary epithelial cell lines. TSA induced the INK4-family genes p18 and p19, whereas the Cip/Kip family gene p21 was stimulated by 1α,25(OH)₂D₃. Chromatin immunoprecipitation and RNA inhibition assays showed that the co-repressor NCoR1 and some HDAC family members complexed un-liganded VDR and repressed the basal level of CDKI genes, but their role in regulating CDKI gene expression by TSA and 1α,25(OH)₂D₃ were contrary. HDAC3 and HDAC7 attenuated 1α,25(OH)₂D₃-dependent induction of the p21 gene, for which NCoR1 is essential. In contrast, TSA-mediated induction of the p18 gene was dependent on HDAC3 and HDAC4, but was opposed by NCoR1 and un-liganded VDR. This suggests that the attenuation of the response to TSA by NCoR1 or that to 1α,25(OH)₂D₃ by HDACs can be overcome by their combined application achieving maximal induction of anti-proliferative target genes.