title: Histone H3 acetylation is associated with reduced p21(WAF1/CIP1) expression by gastric carcinoma.
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 p21(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 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 p21(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. p21(WAF1/CIP1) mRNA levels were associated with histone H3 acetylation status in the p21(WAF1/CIP1) promoter region (p = 0.047) but not p53 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 p21(WAF1/CIP1) promoter region. Hyperacetylation of histone H4 in the p21(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. 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(WAF1/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.
authors.affiliation: Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Mitani
authors.forename: Naohide
authors.initials: N
authors.lastname: Oue
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hamai
authors.forename: Phyu Phyu
authors.initials: PP
authors.lastname: Aung
authors.forename: Shunji
authors.initials: S
authors.lastname: Matsumura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakayama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kamata
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
mesh_terms: D000107:Acetylation; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004252:DNA Mutational Analysis; D016158:Genes, p53; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm