tubacin and Urinary-Bladder-Neoplasms

Although trimodality therapy resecting tumours followed by chemoradiotherapy is emerged for muscle-invasive bladder cancer (MIBC), chemotherapy produces toxicities. Histone deacetylase inhibitors have been identified as an effective strategy to enhance cancer radiotherapy (RT).. We examined the role of HDAC6 and specific inhibition of HDAC6 on BC radiosensitivity by performing transcriptomic analysis and mechanism study.. HDAC6 knockdown or HDAC6 inhibitor (HDAC6i) tubacin exerted a radiosensitizing effect, including decreased clonogenic survival, increased H3K9ac and α-tubulin acetylation, and accumulated γH2AX, which are similar to the effect of panobinostat, a pan-HDACi, on irradiated BC cells. Transcriptomics of shHDAC6-transduced T24 under irradiation showed that shHDAC6 counteracted RT-induced mRNA expression of CXCL1, SERPINE1, SDC1 and SDC2, which are linked to cell migration, angiogenesis and metastasis. Moreover, tubacin significantly suppressed RT-induced CXCL1 and radiation-enhanced invasion/migration, whereas panobinostat elevated RT-induced CXCL1 expression and invasion/migration abilities. This phenotype was significantly abrogated by anti-CXCL1 antibody, indicating the key regulator of CXCL1 contributing to BC malignancy. Immunohistochemical evaluation of tumours from urothelial carcinoma patients supported the correlation between high CXCL1 expression and reduced survival.. Unlike pan-HDACi, the selective HDAC6i can enhance BC radiosensitization and effectively inhibit RT-induced oncogenic CXCL1-Snail-signalling, thus further advancing its therapeutic potential with RT.

Topics: Acetylation; Carcinoma, Transitional Cell; Cell Line, Tumor; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Panobinostat; Radiation Tolerance; Tubulin; Urinary Bladder Neoplasms

Epigenetic modifiers such as histone deacetylases (HDACs) have come into focus as novel drug targets for cancer therapy due to their functional role in tumor progression. Since common pan-HDAC inhibitors have adverse side effects and minor anti-cancer activity against solid tumors, enzyme-specific inhibitors were developed. HDAC6 is especially well-suited for specific inhibition due to its unique domain structure and mode of action and has been suggested to provide an exceptionally suitable target for cancer therapy. However, expression and function of HDACs have been insufficiently studied in urothelial cancers (UC), a disease urgently requiring new therapeutic approaches. The present study sought to evaluate HDAC6 as a target for treatment of urothelial cancers with enzyme-specific inhibitors. We observed moderate HDAC6 overexpression in urothelial cancer tissues and a broad range of expression in urothelial cancer cell lines. In the cell lines Tubacin was the most potent inhibitor, compared with Tubastatin and ST-80, but still active only at high micromolar concentrations. HDAC6 expression levels correlated poorly with sensitivity to enzyme inhibition. Combined treatments with heat shock, HSP90 inhibition by 17-AAG, proteasome inhibition by bortezomib, or DNA-damaging agents did not result in significant synergistic effects. Experiments with siRNA-mediated knockdown further underlined that urothelial cancer cells do not critically depend on HDAC6 expression for survival.

Topics: Acetylation; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Benzoquinones; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Gene Expression; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Indoles; Inhibitory Concentration 50; Lactams, Macrocyclic; Middle Aged; Protein Processing, Post-Translational; Pyrazines; Urinary Bladder Neoplasms; Urothelium

Histone deacetylase 6 (HDAC6) promotes cell motility and contributes to the metastasis of cancers. The purpose of this study was to investigate the role of HDAC6 in human bladder cancer for the first time. The results showed that HDAC6 promotes the migration and invasion of bladder cancer cells by targeting the cytoskeletal protein cortactin. Furthermore, a colony formation assay as well as in vitro migration and invasion assays demonstrated that this migration and invasion was suppressed by the HDAC6-specific inhibitor tubacin. In addition, cortactin is the substrate of SIRT2, which also belongs to the family of histone deacetylases. We demonstrated that by using SIRT2-specific siRNA combined with tubacin treatment, the cell migratory and invasive abilities were dramatically suppressed. Taken together, we conclude that HDAC6 and SIRT2 work synergistically to promote cell migration and invasion in bladder cancer, and the HDAC6-specific inhibitor tubacin may be regarded as a novel therapeutic agent for bladder cancer.

Topics: Anilides; Cell Line, Tumor; Cell Movement; Cortactin; Down-Regulation; Gene Knockdown Techniques; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Neoplasm Invasiveness; RNA, Small Interfering; Sirtuin 2; Urinary Bladder Neoplasms