Distinct HDACs regulate the transcriptional response of human cyclin-dependent kinase inhibitor genes to Trichostatin A and 1alpha,25-dihydroxyvitamin D3.
The anti-proliferative effects of histone deacetylase (HDAC) inhibitors and 1alpha,25-dihydroxyvitamin D3 [1alpha,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 1alpha,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 1alpha,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 1alpha,25(OH)2D3 were contrary. HDAC3 and HDAC7 attenuated 1alpha,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 1alpha,25(OH)2D3 by HDACs can be overcome by their combined application achieving maximal induction of anti-proliferative target genes.
Malinen
Marjo
M
Department of Biochemistry, University of Kuopio, FIN-70211 Kuopio, Finland.
Saramäki
Anna
A
Ropponen
Antti
A
Degenhardt
Tatjana
T
Väisänen
Sami
S
Carlberg
Carsten
C
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D056971:Nuclear Receptor Co-Repressor 1; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D002843:Chromatin; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; C012589:trichostatin A; D006655:Histone Deacetylases; D002117:Calcitriol