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Acetylation of histones associated with the p21 WAF1/CIP1 gene by butyrate is not sufficient for p21 WAF1/CIP1 gene transcription in human colorectal adenocarcinoma cells
Author(s) -
Kobayashi Hanako,
Tan Er Mei,
Fleming Sharon E.
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11697
Subject(s) - sodium butyrate , acetylation , chromatin immunoprecipitation , histone , microbiology and biotechnology , histone h4 , hdac1 , biology , histone h3 , sap30 , hdac4 , histone deacetylase inhibitor , histone h2a , histone deacetylase 5 , histone deacetylase , hdac8 , cancer research , promoter , gene expression , biochemistry , gene
Abstract 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 p21 WAF1/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 p21 WAF1/CIP1 mRNA in both the absence and the presence of NaB without influencing the butyrate‐induced hyperacetylation of H3 and H4 associated with the p21 WAF1/CIP1 promoter. These results suggest that acetylation of histones at the p21 WAF1/CIP1 promoter is not sufficient for NaB to exert antiproliferative effects via transcription of the p21 WAF1/CIP1 gene. Induction of p21 WAF1/CIP1 transcription by the phosphatase inhibitor, okadaic acid, in the absence of changes in association of acetylated histones with the p21 WAF1/CIP1 promoter provides further evidence of the importance of phosphorylation to p21 WAF1/CIP1 transcription. © 2003 Wiley‐Liss, Inc.