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Tong X , Yin L , Joshi S , Rosenberg DW , Giardina C
Cyclooxygenase-2 regulation in colon cancer cells: Modulation of RNA polymerase II elongation by histone deacetylase inhibitors
Journal of Biological Chemistry. 2005 ;280(16) :15503-15509
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Abstract
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)-?. Moreover, we found that the histone deacetylase inhibitors butyrate and trichostatin A could block Cox-2 activation in a gene-specific manner. TNF-? 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-? increased Cox-2 transcription, whereas butyrate was suppressive. Because butyrate has been reported to suppress polymerase elongation on the c-myc gene, 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-myc and Cox-2 genes. We propose that histone deacetylases regulate a transcriptional block on the Cox-2 and c-myc genes and that this block may be a potential target for pharmacological intervention. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
Notes
00219258 (ISSN) Cited By: 3; Export Date: 25 May 2006; Source: Scopus CODEN: JBCHA; DOI: 10.1074/jbc.M411978200 Language of Original Document: English Correspondence Address: Giardina, C.; Dept. of Molecular and Cell Biology; University of Connecticut; 91 N. Eagleville Rd. Storrs, CT 06269-3125, United States; email: Giardina@uconnvm.uconn.edu Chemicals/CAS: butyric acid, 107-92-6, 156-54-7, 461-55-2; protein, 67254-75-5; trichostatin A, 58880-19-6, Butyrates; cyclooxygenase 2, EC 1.14.99.1; Histone Deacetylases, EC 3.5.1.-; Hydroxamic Acids; Prostaglandin-Endoperoxide Synthase, EC 1.14.99.1; RNA Polymerase II, EC 2.7.7.-; RNA, Messenger; trichostatin A, 58880-19-6; Tumor Necrosis Factor-alpha References: Chung, D.C., (2000) Gastroenterology, 119, pp. 854-865; Gupta, R.A., Dubois, R.N., (2001) Nat. Rev. Cancer, 1, pp. 11-21; Herschman, H.R., (1996) Biochim. Biophys. 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