Abstract
Abstract Butyrate, one of the short chain fatty acids generated in the colon by microbiota from dietary fiber, has shown both preventative and therapeutic potential to counteract inflammatory disease and inflammation-mediated colorectal cancer. GPR109A, a recently identified receptor for butyrate, is highly expressed in normal colonic tissue, but is often down-regulated in human colon carcinoma cells. The molecular mechanisms underlying regulation of GPR109A expression in human colon carcinoma cells is unknown. Here we demonstrated that although there is no CpG island in the human GPR109A promoter region, the GPR109A promoter is hypermethylated in human colon carcinoma cell lines and in colon carcinoma tissue specimens. Interestingly, despite the hypermethylation of the promoter, IFN-γ, a cytokine secreted by activated cytotoxic T lymphocytes (CTL), effectively up-regulated GPR109A expression in human colon carcinoma cells, and this regulation is mediated at the transcriptional level. Furthermore, we demonstrated that the IFN-γ-activated pSTAT1 regulates GPR109A expression by directly binding to the Gamma Activation Site (GAS) elements in the GPR109A promoter region in human colon carcinoma cells. At the functional level, IFN-γ-mediated up-regulation of GPR109A resulted in increased sensitivity of the tumor cells to butyrate-induced cell death and increased level of histone acetylation in human colon carcinoma cells. In summary, our data demonstrated that although GPR109A can be constitutively silenced by DNA methylation in human colon carcinoma cells, tumor-infiltrating CTLs might use secretion of IFN-γ to up-regulate GPR109A as a mechanism to re-activate GPR109A, thereby restoring functional response of colon carcinoma cells to butyrate in the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3140. doi:1538-7445.AM2012-3140
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
