Nucleic Acids Research Advance Access originally published online on November 13, 2007
Nucleic Acids Research 2008 36(1):121-132; doi:10.1093/nar/gkm913
Nucleic Acids Research, 2008, Vol. 36, No. 1 121-132
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1
,25-dihydroxyvitamin D3
1Departments of Biochemistry, 2Clinical Microbiology, University of Kuopio, FIN-70211 Kuopio, Finland and 3Life Sciences Research Unit, University of Luxembourg, L-1511 Luxembourg, Luxembourg
*To whom correspondence should be addressed. Tel: +352 4666446267; Fax: +352 4666446435; Email: carsten.carlberg{at}uni.lu
Received June 13, 2007. Revised September 4, 2007. Accepted October 8, 2007.
The anti-proliferative effects of histone deacetylase (HDAC) inhibitors and 1
,25-dihydroxyvitamin D3 [1,25(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 1,25(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 1,25(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 1,25(OH)2D3 were contrary. HDAC3 and HDAC7 attenuated 1,25(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 1,25(OH)2D3 by HDACs can be overcome by their combined application achieving maximal induction of anti-proliferative target genes.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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