Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1 Journal Article
| Authors: | Gui, C. Y.; Ngo, L.; Xu, W. S.; Richon, V. M.; Marks, P. A. |
| Article Title: | Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1 |
| Abstract: | Histone deacetylase (HDAC) inhibitors (HDACi) cause cancer cell growth arrest and/or apoptosis in vivo and in vitro. The HDACi suberoylanilide hydroxamic acid (SAHA) is in phase I/II clinical trials showing significant anticancer activity. Despite wide distribution of HDACs in chromatin, SAHA alters the expression of few genes in transformed cells. p21WAF1 is one of the most commonly induced. SAHA does not alter the expression of p27 KIPI, an actively transcribed gene, or globin, a silent gene, in ARP-1 cells. Here we studied SAHA-induced changes in the p21WAF1 promoter of ARP-1 cells to better understand the mechanism of HDACi gene activation. Within 1 h, SAHA caused modifications in acetylation and methylation of core histones and increased DNase I sensitivity and restriction enzyme accessibility in the p21WAF1 promoter. These changes did not occur in the p27KIPI or ε-globin gene-related histones. The HDACi caused a marked decrease in HDAC1 and Myc and an increase in RNA polymerase II in proteins bound to the p21WAF1 promoter. Thus, this study identifies effects of SAHA on p21WAF1-associated proteins that explain, at least in part, the selective effect of HDACi in altering gene expression. |
| Keywords: | controlled study; unclassified drug; human cell; promoter region; histone deacetylase inhibitor; multiple myeloma; gene expression; drug effect; cell line, tumor; protein processing, post-translational; drug mechanism; enzyme inhibitors; histone; myc protein; protein p27; globin; vorinostat; hydroxamic acids; gene inactivation; cyclin-dependent kinase inhibitor p21; cyclins; protein p21; rna polymerase ii; histone deacetylases; protein methylation; histone deacetylase; protein modification; acetylation; myc; rna polymerase; cell strain; suberoylanilide hydroxamic acid; cyclin dependent kinase inhibitor 1; promoter regions (genetics); deoxyribonuclease i; humans; human; priority journal; article; epsilon globin; protein p27 kipi; cell strain arp 1 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 101 |
| Issue: | 5 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2004-02-03 |
| Start Page: | 1241 |
| End Page: | 1246 |
| Language: | English |
| DOI: | 10.1073/pnas.0307708100 |
| PROVIDER: | scopus |
| PMCID: | PMC337037 |
| PUBMED: | 14734806 |
| DOI/URL: | |
| Notes: | Proc. Natl. Acad. Sci. U. S. A. -- Cited By (since 1996):322 -- Export Date: 16 June 2014 -- CODEN: PNASA -- Source: Scopus |
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