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J. Biol. Chem., Vol. 280, Issue 16, 15503-15509, April 22, 2005

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Cyclooxygenase-2 Regulation in Colon Cancer Cells

MODULATION OF RNA POLYMERASE II ELONGATION BY HISTONE DEACETYLASE INHIBITORS^*

Xin Tong, Lei Yin¶, Shree Joshi, Daniel W. Rosenberg||, and Charles Giardina**

From the Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269-3125, ^¶Department of Endocrinology and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ^||Department of Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030

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.

Received for publication, October 21, 2004 , and in revised form, February 7, 2005.

^* This work was supported by NCI Grant R29 CA79656-01 from the National Institutes of Health (to C. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111-2497.

^** To whom correspondence should be addressed: Dept. of Molecular and Cell Biology, 91 N. Eagleville Rd., University of Connecticut, Storrs, CT 06269-3125. Tel.: 860-486-0089; Fax: 860-486-4331; E-mail: Giardina{at}uconnvm.uconn.edu.

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