Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat

Abstract

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 anchoragedependent growth capacities. Pracinostat also induced growth arrest at the G 0 -G 1 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.

ATF3 Repression of BCL-XL Determines Apoptotic Sensitivity to HDAC Inhibitors across Tumor Types

“…Furthermore, ATF3 is required for apoptosis induced by ER stress (37), anoxia (38), and the chemotherapeutic agents 5FU, etoposide and cisplatin (39–41). Finally, ATF3 is required for apoptotic sensitization to HDACi combination therapy with cisplatin and agonistic anti-DR5 antibodies (41,42) and for HDACi-induced apoptosis in bladder cancer cells (43). However the subsequent mechanisms of apoptosis induction have not been investigated.…”

“…Prior studies have linked HDACi-induced apoptosis with altered expression of a number of pro- and anti-apoptotic genes, particularly components of the intrinsic apoptotic pathway (43). However, these effects have not been investigated in the context of sensitivity across tumour cell type, and the mechanisms which underpin altered expression of these genes have not been systematically addressed.…”

ATF3 inhibits the tumorigenesis and progression of hepatocellular carcinoma cells via upregulation of CYR61 expression

“…In bladder cancer, ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton [ 11 ]. Reactivation of ATF3 by pracinostat is a determining factor in the tumor response to the HDACi therapy and ATF3 was a biomarker of tumor response [ 29 ]. On the other hand, upregulation of ATF3 in lung cancer could promote cell proliferation, migration, and invasion [ 30 ].…”

Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice

“…Indeed, although it was first identified as a metastasis-promoting gene in a mouse model of melanoma 41 , ATF3 has recently been shown to suppress growth and/or progression of colon 42 , bladder 43 , esophageal 25 , prostate 44 , and lung cancers 24 , 45 through diverse mechanisms including inhibition of Akt and cytoskeleton remodeling. It was also frequently reported that ATF3 mediates cytotoxic effects of therapeutic agents such as curcumin 46 , cisplatin 47 , and pracinostat 48 . More recently, ATF3 was shown to sensitize glioma stem cells to proteasome inhibitors 49 – a result supporting the notion that ATF3 can serve as a biomarker for predicting outcomes of targeted anti-cancer therapies.…”