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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Histone deacetylase (HDAC) inhibitor activation of p21~(WAF1) involves changes in promoter-associated proteins, including HDAC1
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Histone deacetylase (HDAC) inhibitor activation of p21~(WAF1) involves changes in promoter-associated proteins, including HDAC1

机译：组蛋白去乙酰化酶（HDAC）抑制剂激活p21〜（WAF1）涉及启动子相关蛋白的变化，包括HDAC1

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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. p21~(WAF1) 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 p21~(WAF1) 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 p21~(WAF1) promoter. These changes did not occur in the p27~(KIPI) 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 p21~(WAF1) promoter. Thus, this study identifies effects of SAHA on p21~(WAF1)-associated proteins that explain, at least in part, the selective effect of HDACi in altering gene expression.
机译：组蛋白脱乙酰基酶（HDAC）抑制剂（HDACi）在体内和体外引起癌细胞生长停滞和/或凋亡。 HDACi辛二酰苯胺异羟肟酸（SAHA）处于I / II期临床试验，显示出显着的抗癌活性。尽管HDAC在染色质中分布广泛，但SAHA改变了转化细胞中少数基因的表达。 p21〜（WAF1）是最常见的一种。 SAHA不会改变ARP-1细胞中活跃转录的基因p27〜（KIPI）或沉默基因globin的表达。在这里，我们研究了SAHA诱导的ARP-1细胞p21〜（WAF1）启动子的变化，以更好地了解HDACi基因激活的机制。在1小时内，SAHA引起核心组蛋白的乙酰化和甲基化修饰，并增加了p21〜（WAF1）启动子中DNase I的敏感性和限制性酶的可及性。这些变化在p27〜（KIPI）或ε-珠蛋白基因相关的组蛋白中未发生。 HDACi在与p21〜（WAF1）启动子结合的蛋白质中引起HDAC1和Myc的显着减少以及RNA聚合酶II的增加。因此，本研究确定了SAHA对p21〜（WAF1）相关蛋白的作用，这至少部分解释了HDACi在改变基因表达中的选择性作用。

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