Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to trichostatin A and 1 alpha,25-dihydroxyvitamin D-3

作者：Malinen Marjo; Saramaki Anna; Ropponen Antti; Degenhardt Tatjana; Vaisanen Sami; Carlberg Carsten^*

来源：Nucleic Acids Research, 2008, 36(1): 121-132.

DOI：10.1093/nar/gkm913

The anti-proliferative effects of histone deacetylase (HDAC) inhibitors and 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] 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 alpha,25(OH)(2)D-3 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 alpha,25(OH)(2)D-3. 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 alpha,25(OH)(2)D-3 were contrary. HDAC3 and HDAC7 attenuated 1 alpha,25(OH)(2)D-3-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 alpha,25(OH)(2)D-3 by HDACs can be overcome by their combined application achieving maximal induction of anti-proliferative target genes.

• 出版日期2008-1