期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：5
页码：1241-1246
DOI：10.1073/pnas.0307708100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 p27KIPI, 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 {epsilon}-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.
