Investigation of the effect of sodium butyrate on the regulation of cyclooxygenase-2 in colon cancer cell lines Caco-2 and HT-29

Ülgen, Doğukan Hazar
Sodium butyrate (NaBt) is a four-carbon short-chain fatty acid histone deacetylase inhibitor (HDACi) that is available in the colon through the commensal microbiota-mediated fermentation of dietary fibers. It is the main source of energy for colonocytes, and is regarded to have tumor suppressive effects, most prominently in colorectal cancer (CRC). Cyclooxygenase-2 (COX-2) is a gene important in the inflammatory response due to its ability to convert arachidonic acid to prostaglandins. Overexpression and overactivity of COX-2 were observed in chronic inflammatory diseases and CRC. To understand whether the expression of COX-2 was regulated through NaBt in CRC, we treated Caco-2 and HT-29 cells with 3mM NaBt. We observed that Caco-2 cells treated with 3 mM NaBt showed increased mRNA and protein expression of COX-2 while a decrease in the same was observed in HT-29 cells. To understand the mechanism behind this dual regulation, we analyzed the transcriptional regulation of COX-2 through NF-κB. Contrary to our v expectations, we found that even though the nuclear localization of p65 subunit of NF-κB showed an increase in Caco-2 cells and not in HT-29 cells, the recruitment of NF-κB to the COX-2 promoter region decreased in Caco-2 cells, and increased in HT-29 cells We therefore hypothesized that COX-2 was regulated post-trascriptionally. We observed that mitogen-activated protein kinase (MAPK) p38, a pathway that activates a number of proteins involved in mRNA stabilization, was activated only in Caco-2 cells and not HT-29 cells. We investigated the downstream signaling and discovered that the use of distal polyadenylation signal, and the stability of COX-2 were increased in NaBt-treated Caco-2 cells and decreased in HT-29 cells. We then showed that the said stability was lost when the p38 activity was inhibited in Caco-2 cells. The stabilizing AU-rich element binding protein (AREBPs) HuR was found to decline in the two cell lines, whereas destabilizing AREBP TTP exhibited a decrease only in Caco-2 cells. Collectively, this study indicates that NaBt can modify the transcriptome not only through its HDACi ability but also via the activation of p38-dependent post-transcriptional regulation networks.


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NaBt can regulate the expression of COX-2 post-transcriptionally in the presence of chemically induced stress in colon epithelial cells.
Banerjee, Sreeparna; Gurbanov, Sinem Tunçer; Ülgen, Dogukan Hazar; Torun, Aydan (null; 2018-04-19)
Sodium butyrate (NaBt) is a histone deacetylase inhibitor (HDACi) produced in the colon by commensal microbiota-mediated fermentation of dietary fibers. It is regarded to have tumor suppressive and anti-inflammatory effects. NaBt can regulate gene expression through chromatin remodeling and altered transcription. However, it has not been addressed adequately whether inflammatory genes may also be regulated by NaBt in a post transcriptional manner via AU rich elements (ARE) in their 3'UTR. Overexpression of ...
Citation Formats
D. H. Ülgen, “Investigation of the effect of sodium butyrate on the regulation of cyclooxygenase-2 in colon cancer cell lines Caco-2 and HT-29,” M.S. - Master of Science, Middle East Technical University, 2015.