Histone deacetylase 8 is deregulated in urothelial cancer but not a target for efficient treatment

Background: previous studies have shown that class-i histone deacetylase (hdac) 8 mrna is upregulated in urothelial cancer tissues and urothelial cancer cell lines compared to benign controls. using urothelial cancer cell lines we evaluated whether specific targeting of hdac8 might be a therapeutic option in bladder cancer treatment. methods. we conducted sirna-mediated knockdown and specific pharmacological inhibition of hdac8 with the three different inhibitors compound 2,compound 5,and compound 6 in several urothelial carcinoma cell lines with distinct hdac8 expression profiles. levels of hdac and marker proteins were determined by western blot analysis and mrna levels were measured by quantitative real-time pcr. cellular effects of hdac8 suppression were analyzed by atp assay,flow cytometry,colony forming assay and migration assay. results: efficient sirna-mediated knockdown of hdac8 reduced proliferation up to 45%. the hdac8 specific inhibitors compound 5 and compound 6 significantly reduced viability of all urothelial cancer cell lines (ic50 9 - 21 μm). flow cytometry revealed only a slight increase in the sub-g1 fraction indicating a limited induction of apoptosis. expression of thymidylate synthase was partly reduced; parp-cleavage was not detected. the influence of the pharmacological inhibition on clonogenic growth and migration show a cell line- and inhibitor-dependent reduction with the strongest effects after treatment with compound 5 and compound 6. conclusions: deregulation of hdac8 is frequent in urothelial cancer,but neither specific pharmacological inhibition nor sirna-mediated knockdown of hdac8 impaired viability of urothelial cancer cell lines in a therapeutic useful manner. accordingly,hdac8 on its own is not a promising drug target in bladder cancer. © 2014 lehmann et al.; licensee biomed central ltd.