Effects of novel HDAC inhibitors on urothelial carcinoma cells
Aline Kaletsch, Maria Pinkerneil, Michèle J. Hoffmann, Ananda A. Jaguva Vasudevan, Chenyin Wang, Finn K. Hansen, Constanze Wiek, Helmut Hanenberg, Christoph Gertzen, Holger Gohlke, Matthias U. Kassack, Thomas Kurz, Wolfgang A. Schulz, Günter Niegisch
Heinrich Heine University, Duesseldorf
Histone deacetylase inhibitors (HDACi) are promising anti-cancer drugs that could also be employed for urothelial carcinoma (UC) therapy. It is unclear, however, whether inhibition of all 11 zinc-dependent HDACs or of individual enzymes is more efficacious and specific. Here, we investigated the novel HDACi 19i (LMK235) with presumed preferential activity against class IIA HDAC4/5 in comparison to the pan-HDACi vorinostat (SAHA) and the HDAC4-specific HDACi TMP269 in UC cell lines with basal expression of HDAC4 and characterized two HDAC4-overexpressing UC cell lines. In UC cell lines, 19i CC50s ranged around 1 μM; control lines were similarly or less sensitive. Like SAHA, 19i increased the G2/M-fraction, disturbed mitosis, and elicited apoptosis or in some cells senescence. Thymidylate synthase expression was diminished, and p21CIP1 was induced; global histone acetylation and α-tubulin acetylation also increased. In most cell lines, 19i as well as SAHA induced HDAC5 and HDAC4 mRNAs while rather repressing HDAC7. UC cell lines overexpressing HDAC4 were not significantly less sensitive to 19i. Reevaluation of the in vitro HDAC isoenzyme activity inhibition profile of 19i and its docking to HDAC4 using current assays suggested rather low activity against class IIA HDACs. The specific class IIA HDAC inhibitor TMP269 impeded proliferation of UC cell lines only at concentrations > 10 μM. Anti-neoplastic effects of 19i on UC cells appear to be exerted by targeting class I HDACs. In fact, HDAC4 may rather impede UC growth. Our results suggest that targeting of class IIA HDACs 4/5 may not be optimal for UC therapy. Moreover, our investigation provides further evidence for cross-regulation of class IIA HDACs by class I HDACs.