HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Archer, S. Y. Articles by Hodin, R. A. Search for Related Content PubMed PubMed Citation Articles by Archer, S. Y. Articles by Hodin, R. A.

LIVER AND BILIARY TRACT

The histone deacetylase inhibitor butyrate downregulates cyclin B₁ gene expression via a p21/WAF-1-dependent mechanism in human colon cancer cells

Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Submitted 3 January 2005 ; accepted in final form 2 June 2005

Histone deacetylase (HDAC) inhibitors are showing promise as treatment for a variety of human cancers, but their precise mechanism of action has not been elucidated. We examined the effects of the HDAC inhibitor butyrate on colon cancer cells, focusing on its effect on the cell cycle promoter cyclin B₁. In HT-29 cells, sodium butyrate-mediated growth inhibition is associated with a marked decrease in cyclin B₁ mRNA levels. The decrease in cyclin B₁ occurred in a delayed fashion (at 24 h), is completely blocked by concomitant treatment with protein synthesis inhibitors, and appears to be dependent on changes in transcription. Cyclin B₁ repression is linked to the differentiation process in colon cancer cells, not merely with growth arrest. The mechanism of cyclin B₁ repression by butyrate requires prolonged histone hyperacetylation and is at least partly dependent on p21 expression. In fact, p21/WAF-1 appears to directly repress a minimal cyclin B₁ promoter (–90 bp), a process that can be mediated by the amino-terminal portion of the p21 protein. These findings highlight key molecular mechanisms by which HDAC inhibitors mediate their beneficial effects on human cancer cells.

short-chain fatty acids; cell cycle; HT-29; Caco-2