Acetylation of histones associated with the p21WAF1/CIP1 gene by butyrate is not sufficient for p21WAF1/CIP1 gene transcription in human colorectal adenocarcinoma cells.
Acetylation of histones associated with the p21WAF1/CIP1 gene by butyrate is not sufficient for p21WAF1/CIP1 gene transcription in human colorectal adenocarcinoma cells.
复制标题
丁酸盐对与 p21WAF1/CIP1 基因相关的组蛋白进行乙酰化不足以促进人结直肠腺癌细胞中 p21WAF1/CIP1 基因的转录。
DOI：
10.1002/ijc.11697
复制
发表时间：
2004
影响因子：
6.4
通讯作者：
Fleming,SharonE
中科院分区：
文献类型：
--
作者：
Kobayashi,Hanako;Tan,ErMei;Fleming,SharonE
丁酸被认为是组蛋白脱乙酰酶(HDAC)的抑制剂，组蛋白乙酰化的变化被认为改变了基因的表达。在染色质水平研究了丁酸钠(NAB)诱导p21WAF1/CIP1的机制，p21WAF1/CIP1是NAB抗增殖作用的关键基因。用染色质免疫沉淀法(ChIP)检测，在NAB作用30min内，组蛋白H3在启动子近端区域发生乙酰化，并在2小时内延伸到远端区域。相反，组蛋白H4在30分钟内在启动子的近端和远端都被乙酰化。NAB不影响其他组蛋白修饰。NAB刺激转录因子ZBP89、Sp1和GCN5的募集，但不影响SP3、HDAC1、p300或CBP的募集。由于HDAC1在启动子上的募集似乎不能解释NAB诱导的组蛋白乙酰化的变化，我们的目的是通过改变其磷酸化状态来影响HDAC的活性。激酶抑制剂H7抑制p21WAF1/CIP1mRNA，但不影响丁酸诱导的与p21WAF1/CIP1启动子相关的H3和H4的超乙酰化。这些结果表明，组蛋白在p21WAF1/CIP1启动子上的乙酰化不足以使NAB通过转录p21WAF1/CIP1基因发挥抗增殖作用。在乙酰化组蛋白与p21WAF1/CIP1启动子的结合没有改变的情况下，由磷酸酶抑制剂冈田酸诱导p21WAF1/CIP1转录，进一步证明了磷酸化对p21WAF1/CIP1转录的重要性。©2003 Wiley-Liss公司
Butyric acid is well recognized as a histone deacetylase (HDAC) inhibitor, and changes in histone acetylation are thought to alter gene expression. The mechanism by which sodium butyrate (NaB) induces p21WAF1/CIP1, a critical gene involved in the antiproliferative effect of NaB, was studied at the chromatin level. Using chromatin immunoprecipitation (ChIP) assay, acetylation of histone H3 was observed at the proximal region of the promoter within 30 min of NaB exposure and this extended to the distal region within 2 hr. By contrast, histone H4 was acetylated both at the proximal and the distal regions of the promoter within 30 min. NaB did not influence other histone modifications. NaB stimulated recruitment of the transcription factors ZBP89 and Sp1 as well as GCN5, but did not influence recruitment of Sp3, HDAC1, p300, or CBP. As recruitment of HDAC1 to the promoter appeared not to account for NaB‐induced changes in histone acetylation, we aimed to influence HDAC activity by altering its phosphorylation status. The kinase inhibitor, H7, suppressed p21WAF1/CIP1mRNA in both the absence and the presence of NaB without influencing the butyrate‐induced hyperacetylation of H3 and H4 associated with the p21WAF1/CIP1promoter. These results suggest that acetylation of histones at the p21WAF1/CIP1promoter is not sufficient for NaB to exert antiproliferative effects via transcription of the p21WAF1/CIP1gene. Induction of p21WAF1/CIP1transcription by the phosphatase inhibitor, okadaic acid, in the absence of changes in association of acetylated histones with the p21WAF1/CIP1promoter provides further evidence of the importance of phosphorylation to p21WAF1/CIP1transcription. © 2003 Wiley‐Liss, Inc.