Histone H3 acetylation is associated with reduced p21WAF1/CIP1 expression by gastric carcinoma
Histone H3 acetylation is associated with reduced p21WAF1/CIP1 expression by gastric carcinoma
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DOI：
10.1002/path.1684
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发表时间：
2005-01-01
影响因子：
7.3
通讯作者：
Yasui, W
中科院分区：
文献类型：
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作者：
Mitani, Y;Oue, N;Yasui, W
组蛋白乙酰化似乎在转录调控中起着重要作用。组蛋白去乙酰化使染色质失活，参与了WAF1/CIP1对包括p21在内的几个肿瘤抑制基因的转录抑制。然而，组蛋白乙酰化在包括胃癌在内的人类癌症中的体内状态还不是很清楚。本研究表明，p21(WAF1)/(CIP1)启动子区域的组蛋白H3发生低乙酰化，并且这种低乙酰化与p21(WAF1/CIP1)在胃癌组织中的表达降低有关。染色质免疫沉淀分析显示，29例胃癌组织中，p21(WAF1)/(CIP1)启动子和编码区的组蛋白H3分别有10例(34.5%)和10例(34.5%)发生低乙酰化。29例胃癌组织中p21(WAF1/CIP1)启动子和编码区有6例(20.7%)和16例(55.2%)组蛋白H4发生低乙酰化。P21(WAF1/CIP1)基因表达水平与p21WAF1/1CIP1启动子区组蛋白H3乙酰化状态相关(P=0.047)，而与p53突变状态无关(P=0.460)。在胃癌细胞系中，组蛋白去乙酰酶抑制剂曲古抑素A可诱导p21(WAF1/CIP1)蛋白表达。这种诱导与组蛋白H3在p21(WAF1/CIP1)启动子区域的超乙酰化有关。组蛋白H4在p21(WAF1/CIP1)启动子区域的超乙酰化似乎与表达增加无关。P21(WAF1/CIP1)蛋白表达的诱导与p21(WAF1/CIP1)编码区组蛋白H3和H4的超乙酰化有关。P21(WAF1/CIP1)蛋白表达下调。在表达显性阴性P53的细胞中，p21(WAF1CIP1)基因启动子和编码区的组蛋白H4乙酰化程度低于表达野生型P53的细胞的一半，而在表达显性阴性P53的细胞中，组蛋白H3在启动子和编码区的乙酰化略有减少(约20%)。这些发现提供了组蛋白乙酰化改变发生在人类癌症组织标本中的证据，例如来自胃癌的标本。版权所有(C)2004年大不列颠和爱尔兰病理学会。作者：John Wiley Sons，Ltd.
Histone acetylation appears to play an important role in transcriptional regulation. Inactivation of chromatin by histone deacetylation is involved in the transcriptional WAF1/CIP1 repression of several tumour suppressor genes, including p 21. However, the in vivo status of histone acetylation in human cancers, including gastric carcinoma, is not well understood. This study shows that histone H3 in the p21 (WAF1)/(CIP1) promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p21 (WAF1/CIP1) expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p 21 (WAF1)/(CIP1) promoter and coding regions in 10 (34.5%) and 10 (34.5%) of 29 gastric carcinoma specimens, respectively. Hypoacetylation of histone H4 in the p21 (WAF1/CIP1) promoter and coding regions was observed in 6 (20.7%) and 16 (55.2 %) of 29 gastric carcinoma specimens, respectively. p 21 (WAF1/CIP1) mRNA levels were associated with histone H3 acetylation status in the p 21 WAF1/1CIP1 promoter region (P = 0.047) but not p53 mutation status (p = 0.460). In gastric carcinoma cell lines, expression of p2l (WAF1/CIP1) protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p21 (WAF1/CIP1) promoter region. Hyperacetylation of histone H4 in the p2l (WAF1/CIP1) promoter region did not appear to be associated with increased expression. Induction of p21(WAF1/CIP1) protein expression was associated with hyperacetylation of histones H3 and H4 in the p21 (WAF1/CIP1) coding region. ly Expression of a dominant-negative mutant of p53 reduced expression of p21(WAF1/CIP1) protein. Histone H4 acetylation in both the promoter and coding regions of the p21 (WAF1CIP1) gene in cells expressing dominant-negative p53 was less than half of that in cells expressing wild-type p53, whereas histone H3 acetylation in both the promoter and coding regions was slightly reduced (by approximately 20%) in cells expressing the dominant-negative p53. These findings provide evidence that alteration of histone acetylation occurs in human cancer tissue specimens such as those from gastric carcinoma. Copyright (C) 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.