p21 ^WAF1 is required for butyrate-mediated growth inhibition of human colon cancer cells

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 postconf luent 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.

The effects of trichostatin A on the oncolytic ability of herpes simplex virus for oral squamous cell carcinoma cells

“…17 With regard to the cell cycle, the growth inhibition mediated by HDACi in human tumor cells is primarily due to an induction of p21 expression, with a subsequent inhibition of cyclin/cyclin-dependent kinase (CDK) activity. 30,31 We found that TSA induced the expression of p21 and arrested the cell cycle at G1 in oral SCC cells. This must contribute to the enhanced suppression of cell viability in cultures treated with a combination of R849 and TSA.…”

“…30,31 R849-infected SAS cells were treated with TSA. Immunoblot analysis revealed that p21 became detectable in cells treated with TSA.…”

Effects of demethylating agent 5-aza-2′-deoxycytidine and histone deacetylase inhibitor FR901228 on maspin gene expression in oral cancer cell lines

“…Only a few target genes whose expression is upregulated in response to HDAC inhibitor-mediated growth arrest have been identified, e.g., the cyclin-dependent kinase inhibitors p21/WAF1 [23][24][25], c-myc [26,27], and the anti-apoptotic bcl-2 gene [28,29]. Among the latest reports, Butler et al have found that Suberoylanilide hydroxamic acid (SAHA), one of the HDAC inhibitors, induces expression of the thioredoxin-binding protein-2 (TBP-2) gene in LNCaP prostate cells [30].…”

Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53

“…SAHA, like the four-carbon short-chain fatty acid butyrate (Archer et al, 1998), functions as an inhibitor of histone deacetylase (HDI) (Richon et al, 1998), an enzyme implicated in regulation of histone acetylation and genes implicated in cellular maturation (Ogryzko et al, 1996). Given the close relationship that exists between di erentiation and apoptosis (Martin et al, 1990), it is plausible that SAHA also induces genes involved in the cell death program.…”