P130 HISTONE DEACETYLASES EXPRESSION AND ACTIVITY IN ESOPHAGEAL ADENOCARCINOMA CELLS IN VITRO

Abstract

Abstract Aim The response of EAC patients to common chemotherapeutic regimens is relatively low (approx. 50%). Improving the response rate in cancer patients is challenging and novel therapeutic treatment options are needed. Histone deacetylases (HDAC), an enzyme class with promising novel features, are involved the regulation of gene expression affecting the epigenom. Methods The expression of Zn2+-dependent HDACs and the endogenous HDAC activity were characterized in a Berrett’s esophagus in vitro model, containing cells from squamous epithelium, Barrett’s metaplasia, dysplasia and EAC. Proliferation assays were carried out in EAC cells to determine cell response to an experimental, HDAC1-3 specific, HDAC inhibitor (HDACi) in comparison to vorinostat (pan HDACi). The HDAC activity, the p21 expression, and the histone H3 acetylation were investigated under HDACi treatment. Results All Zn2+-dependent HDACs were expressed by each stage of the Berrett’s esophagus in vitro model. However, the expression intensity was variable. Vorinostat showed an inhibition of proliferation in the EAC cells OE33 and OE19 (IC50 of 1.1μM and 1.8μM), while the experimental HDACi DDK137 revealed an increased anti proliferative effect (IC50 of 0.4μM and 0.6μM), a higher HDAC activity reduction, and higher increase in H3 acetylation. The p21 mRNA-expression showed a cell line, time and inhibitor specific increase. The highest increase was determined in OE33 cells (2.5fold) by DDK137 after 48h, while no increase in p21 was measured under vorinostat treatment. Conclusion We could show a pharmacological more potent HDACi than vorinostat in EAC cells in vitro. However, further studies are necessary to evaluate the significance of HDACi and whether HDACi are able to increase chemosensitivity in EAC patients.