Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects
Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects
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DOI：
10.1074/jbc.274.49.34940
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发表时间：
1999-12-03
影响因子：
4.8
通讯作者：
Cohen, D
中科院分区：
文献类型：
--
作者：
Sambucetti, LC;Fischer, DD;Cohen, D
组蛋白乙酰化正在成为一种主要的调控机制，被认为可以通过改变转录因子与 DNA 的可及性来调节基因表达。在这项研究中，用组蛋白脱乙酰酶抑制剂 trapoxin (TPX) 处理人类肿瘤细胞，导致控制细胞周期的基因发生选择性变化。 TPX 激活 p21(waf1) 转录，导致三种人类肿瘤细胞系中 p21(waf1) 蛋白水平升高，而不改变 cdk2、cdk4 或细胞周期蛋白 B 的蛋白水平。此外，TPX 增加细胞周期蛋白 E 转录，而不增加 Rb、E2F、二氢叶酸还原酶或 3-磷酸甘油醛脱氢酶的水平。p21(waf1) 蛋白水平升高导致 Rb 降低磷酸化和 cdk2 活性。这些效应导致 H1299 人肺癌细胞和 MDA-MB-435 乳腺癌细胞中 G(1) 和 G(2) 细胞周期停滞，以及 A549 肺癌细胞中细胞凋亡。染色质免疫沉淀分析显示，TPX 增加了 p21(waf1) 启动子 trapoxin 响应区域中与组蛋白 H3 相关的染色质乙酰化水平。这项研究表明，TPX 对 HDAC 的抑制会增加 H3 相关染色质的乙酰化，并以显着的选择性改变基因表达。
Histone acetylation is emerging as a major regulatory mechanism thought to modulate gene expression by altering the accessibility of transcription factors to DNA. In this study, treatment of human tumor cells with the histone deacetylase inhibitor, trapoxin (TPX), resulted in selective changes in genes that control the cell cycle. TPX activated p21(waf1) transcription that led to elevated p21(waf1) protein levels in three human tumor cell lines without altering the protein levels of cdk2, cdk4, or cyclin B, In addition, TPX increased cyclin E transcription without increasing the levels of Rb, E2F, dihydrofolate reductase, or glyceraldehyde-3-phosphate dehydrogenase, The elevated levels of p21(waf1) protein led to decreased Rb phosphorylation and cdk2 activity. These effects resulted in G(1) and G(2) cell cycle arrest in H1299 human lung and MDA-MB-435 breast carcinoma cells and apoptosis in A549 lung carcinoma cells. Chromatin immunoprecipitation assays revealed that TPX increased the level of chromatin acetylation associated with histone H3 in the trapoxin-responsive region of the p21(waf1) promoter. This study demonstrates that inhibition of HDAC by TPX increases acetylation of H3-associated chromatin and alters gene expression with marked selectivity.