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Role of butyrate in post-transcriptional regulation of inflammatory genes by regulating RNA binding proteins

Torun, Aydan
Short chain fatty acids (SCFAs) are generated in the gut by commensal bacteria and are known to reduce inflammation by inhibiting the expression of inflammatory mediators. There are indications that SCFAs can also affect gene expression post transcriptionally. We have hypothesized that butyric acid, a SCFA, can mediate the post-transcriptional regulation of inflammatory mediators such as Cyclooxygenase-2 (COX-2) by affecting the global expression or cytoplasmic translocation of RNA binding proteins (RBPs). We treated colorectal cancer cell lines with sodium butyrate (NaBt) and observed that butyrate reduced the general protein expression of various RBPs and inhibited the cytoplasmic translocation of the stabilizing RBP, HuR. This was supported by a reduction in the NanoLuc reporter activity of several different AU- rich element (ARE) sequences when treated with butyrate and this reduction was maintained even when HuR was overexpressed. We showed that the observed reduced activity of HuR was a consequence of a decrease in p38 and MK2 phosphorylation and increased phosphorylation of Chk2 due to butyrate treatment. Our results suggest that butyrate can reduce the expression of inflammatory genes not only transcriptionally but also post-transcriptionally by affecting the subcellular localization or expression of mRNA stabilizing proteins.