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

Journal of Experimental & Clinical Cancer Research

Günter Niegisch¹  Wolfgang A Schulz¹  Scott M Ulrich²  Annemarie Koch¹  Michèle J Hoffmann¹  Maria Lehmann¹ 

[1] Department of Urology, Heinrich-Heine-University, Medical Faculty, Moorenstr. 5, Duesseldorf 40225, Germany;Department of Chemistry, Ithaca College, Ithaca 14850, NY, USA

关键词: Cell cycle arrest;    Urothelial bladder cancer;    Histone deacetylase inhibitor;    Histone deacetylase 8;   

Others  :  1136197
DOI  :  10.1186/s13046-014-0059-8

 received in 2014-04-29, accepted in 2014-06-27,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Lehmann et al.; licensee BioMed Central Ltd

【 图 表 】

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