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PMID: 9618491 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

p21(WAF1) is required for butyrate-mediated growth inhibition of human colon cancer cells.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 12 ·1998-06-09 ·Pages 6791-6

Archer SY, Meng S, Shei A, Hodin RA

Abstract

A diet high in fiber is associated with a decreased incidence and growth of colon cancers. Butyrate, a four-carbon short-chain fatty acid product of fiber fermentation within the colon, appears to mediate these salutary effects. We sought to determine the molecular mechanism by which butyrate mediates growth inhibition of colonic cancer cells and thereby to elucidate the molecular link between a high-fiber diet and the arrest of colon carcinogenesis. We show that concomitant with growth arrest, butyrate induces p21 mRNA expression in an immediate-early fashion, through transactivation of a promoter cis-element(s) located within 1.4 kb of the transcriptional start site, independent of p53 binding. Studies using the specific histone hyperacetylating agent, trichostatin A, and histone deacetylase 1 indicate that growth arrest and p21 induction occur through a mechanism involving histone hyperacetylation. We show the critical importance of p21 in butyrate-mediated growth arrest by first confirming that stable overexpression of the p21 gene is able to cause growth arrest in the human colon carcinoma cell line, HT-29. Furthermore, using p21-deleted HCT116 human colon carcinoma cells, we provide convincing evidence that p21 is required for growth arrest to occur in response to histone hyperacetylation, but not for serum starvation nor postconfluent growth. Thus, p21 appears to be a critical effector of butyrate-induced growth arrest in colonic cancer cells, and may be an important molecular link between a high-fiber diet and the prevention of colon carcinogenesis.

MeSH Terms
Butyrates/pharmacology Butyric Acid Cell Division/drug effects,genetics Colonic Neoplasms/genetics,pathology Cyclin-Dependent Kinase Inhibitor p21 Cyclins/genetics Gene Expression Regulation, Neoplastic/drug effects Histone Deacetylase Inhibitors Humans Tumor Cells, Cultured
Chemicals
Butyrates CDKN1A protein, human Cyclin-Dependent Kinase Inhibitor p21 Cyclins Histone Deacetylase Inhibitors Butyric Acid
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Archer S Y
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Meng S
Shei A
Hodin R A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.12.6791
Published
1998-06-09
Pages
6791-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC22637
Subset
IM
Grants
NIDDK NIH HHS · R01 DK047186 · United States
NIDDK NIH HHS · DK50623 · United States
NIDDK NIH HHS · DK47186 · United States
NIGMS NIH HHS · GM07806 · United States
NIDDK NIH HHS · R01 DK050623 · United States
NIGMS NIH HHS · T32 GM007806 · United States
External Links
PubMed source DOI: 10.1073/pnas.95.12.6791 PMC Full Text View journal details
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