Inhibition of class I histone deacetylases 1 and 2 promotes urothelial carcinoma cell death by various mechanisms

Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma (UC). To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy of UC siRNA-mediated knockdown and specific pharmacological inhibition of HDAC1 and HDAC2 was applied in UC cell lines (UCCs) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by western blotting and quantitative real-time PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays, flow cytometry, senescence and LDH cytotoxity assays, and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80 % and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line- and HDAC-dependently reduced with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors Romidepsin and Givinostat, significantly reduced proliferation of all UCCs (IC50 3.36 nM - 4.59 µM). Romidepsin and Givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on non-tumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and non-apoptotic cell death in UCCs. Thus, while both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for UC therapy.

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