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ATF3 expression as a marker of response to histone deacetylase inhibition of bladder cancer progression

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thesis
posted on 02.03.2017, 02:58 by Sooraj, Dhanya
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 clinical survival. This study investigated the utility of measuring ATF3 expression as marker of response to the HDACi Pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated expression of ATF3, correlating with significant alteration in proliferative, migratory and anchorage-dependent growth capacities. Pracinostat induced growth arrest at the G0/G1 cell cycle phase, coincident with activation of tumor suppressor genes. Pracinostat treatment also induced sensitivity of bladder cancer cells to chemotherapy in vitro. In mouse xenograft bladder cancer models, Pracinostat treatment significantly reduced tumor volumes compared to controls, accompanied by re-expression of ATF3 in non-proliferating cells from early to late stage of therapy, and in parallel induced anti-angiogenesis 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. This study also identified a potential target of ATF3 - RB1, a key tumor suppressor, in regulating the non-malignant phenotype. Mechanistic studies revealed that overexpression of ATF3 upregulated RB1 expression, concomitant with cell cycle arrest. I conclude that the reactivation of ATF3 is pivotal 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.

History

Principal supervisor

Bryan Williams

Additional supervisor 1

Dakang Xu

Year of Award

2016

Department, School or Centre

Clinical Sciences at Monash Health. Molecular and Translational Science

Campus location

Australia

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences