Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition.
Cox-2 plays an important role in colon carcinogenesis and inflammation. Studying the HT-29 colon cancer cell line as a model, we found that Cox-2 expression and activity is increased approximately 25-fold by TNF-alpha. As previously reported for other Cox-2 inducers, this activation appears to result from a p38-mediated mRNA stabilization rather than an increase in promoter activity. The HDAC inhibitors butyrate and TSA blocked the TNF-alpha activation of Cox-2 protein and mRNA synthesis, and dramatically suppressed Cox-2 activity in HT-29 cells. The suppression of Cox-2 synthesis did not involve promoter inactivation and could be achieved even when applied after the TNF-alpha stimulus. The effect of the HDAC inhibitors was observed prior to the activation of p21 expression and did not require new protein synthesis. Finally, butyrate did not prevent p38 phosphorylation, so the block is likely to occur at a later step in the activation pathway. We propose that a component of the cytokine-induced Cox-2 mRNA stabilization pathway is sensitive to acetylation.
Tong
Xin
X
Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
Yin
Lei
L
Giardina
Charles
C
D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism*; D051546:Cyclooxygenase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007527:Isoenzymes / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C012589:trichostatin A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D006655:Histone Deacetylases