Histone H3 acetylation is associated with reduced p21WAF1/CIP1 expression by gastric carcinoma

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Abstract
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 p21WAF1/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 p21WAF1/CIP1 promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p21WAF1/CIP1 expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p21WAF1/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 p21WAF1/CIP1 promoter and coding regions was observed in 6 (20.7%) and 16 (55.2%) of 29 gastric carcinoma specimens, respectively. p21WAF1/CIP1 mRNA levels were associated with histone H3 acetylation status in the p21WAF1/CIP1 promoter region (p = 0.047) but not p53 mutation status (p = 0.460). In gastric carcinoma cell lines, expression of p21WAF1/CIP1 protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p21WAF1/CIP1 promoter region. Hyperacetylation of histone H4 in the p21WAF1/CIP1 promoter region did not appear to be associated with increased expression. Induction of p21WAF1/CIP1 protein expression was associated with hyperacetylation of histones H3 and H4 in the p21WAF1/CIP1 coding region. Expression of a dominant‐negative mutant of p53 reduced expression of p21WAF1/CIP1 protein. Histone H4 acetylation in both the promoter and coding regions of the p21WAF1/CIP1 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.