We are interested in the mechanism of cyclooxygenase-2 (Cox-2) regulation in colon cancer cells because this knowledge could provide insight into colon carcinogenesis and suggest ways to suppress Cox-2 expression in colon tumors. Studying the HT-29 colon cancer cell line as a model, we found that Cox-2 mRNA and protein levels were activated over 10-fold by the inflammatory cytokine tumor necrosis factor (TNF)-α. Moreover, we found that the histone deacetylase inhibitors butyrate and trichostatin A could block Cox-2 activation in a gene-specific manner. TNF-α and butyrate did not significantly affect Cox-2 promoter activity, mRNA stability, or negative regulation by the Cox-2 3′-untranslated RNA region. A nuclear run-on assay showed that TNF-α increased Cox-2 transcription, whereas butyrate was suppressive. Because butyrate has been reported to suppress polymerase elongation on the c-mycgene, we employed the chromatin immunoprecipitation assay to determine the influence of butyrate and trichostatin A on polymerase distribution on the Cox-2 gene. These data indicated that butyrate restricted polymerase elongation from exon 1 to 2 on both the c-mycand Cox-2 genes. We propose that histone deacetylases regulate a transcriptional block on the Cox-2 and c-mycgenes and that this block may be a potential target for pharmacological intervention.
Proteinase‐activated receptor (PAR)‐2 stimulates cyclooxygenase‐2 (COX‐2) expression in Caco‐2 colon cancer cells: role of matrix metalloproteinases (MMPs)