Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat
Autor: | Bryan R.G. Williams, Jason E. Cain, Dakang Xu, Daniel P. Gold, Dhanya Sooraj |
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Rok vydání: | 2016 |
Předmět: |
Transcriptional Activation
0301 basic medicine Cancer Research Cell Survival Pracinostat medicine.drug_class Activating transcription factor Antineoplastic Agents Apoptosis Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Movement Cell Line Tumor medicine Animals Humans Gene knockdown Activating Transcription Factor 3 Bladder cancer Cell Cycle Histone deacetylase inhibitor Cancer Cell Cycle Checkpoints Cell cycle medicine.disease Xenograft Model Antitumor Assays Histone Deacetylase Inhibitors Disease Models Animal 030104 developmental biology Gene Expression Regulation Urinary Bladder Neoplasms Oncology chemistry 030220 oncology & carcinogenesis Neoplastic Stem Cells Cancer research Benzimidazoles Female Histone deacetylase Biomarkers |
Zdroj: | Molecular Cancer Therapeutics. 15:1726-1739 |
ISSN: | 1538-8514 1535-7163 |
Popis: | Improved treatment strategies are required for bladder cancer due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression and correlates with poor survival. We investigated the utility of measuring ATF3 expression as a marker of response to the HDACi pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated the expression of ATF3, correlating with significant alteration in proliferative, migratory, and anchorage-dependent growth capacities. Pracinostat also induced growth arrest at the G0–G1 cell-cycle phase, coincident with the activation of tumor suppressor genes. In mouse xenograft bladder cancer models, pracinostat treatment significantly reduced tumor volumes compared with controls, accompanied by reexpression of ATF3 in nonproliferating cells from early to late stage of therapy and in parallel induced antiangiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus, reactivation of ATF3 is an important factor in determining sensitivity to pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer. Mol Cancer Ther; 15(7); 1726–39. ©2016 AACR. |
Databáze: | OpenAIRE |
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