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Histone H3 acetylation is associated with reduced p21 WAF1/CIP1 expression by gastric carcinoma
Author(s) -
Mitani Yoshitsugu,
Oue Naohide,
Hamai Yoichi,
Aung Phyu Phyu,
Matsumura Shunji,
Nakayama Hirofumi,
Kamata Nobuyuki,
Yasui Wataru
Publication year - 2005
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1684
Subject(s) - trichostatin a , chromatin immunoprecipitation , histone h3 , microbiology and biotechnology , histone , histone h4 , acetylation , cancer research , histone deacetylase , histone h2a , sap30 , hdac4 , biology , histone deacetylase 5 , hdac11 , gene expression , promoter , gene , biochemistry
Histone acetylation appears to play an important role in transcriptional regulation. Inactivation of chromatin by histone deacetylation is involved in the transcriptional repression of several tumour suppressor genes, including p 21 WAF1/CIP1 . 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 p 21 WAF 1/ CIP 1 promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p 21 WAF 1/ CIP 1 expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p 21 WAF 1/ CIP 1 promoter and coding regions in 10 (34.5%) and 10 (34.5%) of 29 gastric carcinoma specimens, respectively. Hypoacetylation of histone H4 in the p 21 WAF 1/ CIP 1 promoter and coding regions was observed in 6 (20.7%) and 16 (55.2%) of 29 gastric carcinoma specimens, respectively. p 21 WAF 1/ CIP 1 mRNA levels were associated with histone H3 acetylation status in the p 21 WAF 1/ CIP 1 promoter region ( p = 0.047) but not p 53 mutation status ( p = 0.460). In gastric carcinoma cell lines, expression of p21 WAF1/CIP1 protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p 21 WAF 1/ CIP 1 promoter region. Hyperacetylation of histone H4 in the p 21 WAF 1/ CIP 1 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 p 21 WAF 1/ CIP 1 coding region. 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 p 21 WAF 1/ CIP 1 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 © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.