Prostate cancer (PCa) is the second leading cause of cancer-related mortality in American men. Androgen ablation therapies are initially effective in ~90% of patients. Unfortunately, these therapies offer only a temporary relief and the disease eventually recurs with a lethal outcome. PCa that relapsed after hormonal therapies is the major cause of disease lethality and is referred to as castration-resistant PCa (CRPC). A better understanding of mechanisms that control AR activation and allow CRPC to circumvent hormonal ablation therapies is critically important for improving disease outcome. Identification of activators or mediators of AR signaling should help to reveal novel targeted and combinatorial regimens for clinical management of CRPC. Aberrant AR activation in CRPC is achieved via several mechanisms, including gain-of-function mutation. This new-identified molecular mechanism of persistent AR signaling activity is based on expression of AR variants with deletion of ligand-binding domain (AR?LBD); indeed, CRPC that express AR?LBDs are resistant to hormone withdrawal. Due to the constant nuclear localization, AR?LBDs are persistently active for transcription regulation of AR-dependent genes. The goal of this project is to characterize novel targets and to identify new approaches for pharmacological intervention of AR?LBD signaling for CRPC treatment. Transcriptional control of AR-induced genes is regulated by epigenetic modifications of chromatin. The histone variants barcode hypothesis is based on differences between histone variants, and postulates that incorporation of transcription-associated H3.3 and H2A.Z variants creates active territories of chromatin. While the details of these processes are largely unknown, several recent findings and our unpublished data have provided clues: 1) Nuclear protein Daxx and its interactors ATRX and p400 chaperone histone H3 variant, H3.3, and H2A variant, H2A.Z, facilitating formation of transcriptionally active chromatin; 2) both AR and AR?LBD interact with Daxx, recruiting Daxx-containing histone chaperone complexes to ARE in PCa and CRPC; 3) Elevated expressions of Daxx and H2A.Z are associated with bad prognoses of PCa; 4) characterizing expression profiles of genome-edited AR?LBD CRPC cell models, we identified genes that are co-regulated by AR?LBD and Daxx. These findings allowed us to formulate the main hypothesis of this proposal: Constant and uncontrolled recruitment of histone chaperone Daxx by AR?LBDs elevates incorporation of transcription-associated histone variants H3.3 and H2A.Z to ARE, thus modifying expression profile for CRPC progression. Thus, Daxx is potential contributor of CRPC, and Daxx/AR interaction can be investigated as a target for therapeutic intervention, specifically in AR gain-of-function CRPC. In this exploratory grant, we will: I. Evaluate role of histone variants H3.3 and H2A.Z in CRPC; II. Explore mechanisms underlying histone variants H3.3/H2A.Z profiling in CRPC; III. Investigate mechanisms of chaperone recruitment for identification of new therapeutic targets in CRPC. To make progress in PCa treatment, we must develop evidence-based strategies for choosing therapy interventions. If Daxx/AR?LBD were shown to have a role in regulating CRPC progression, this complex would be further highlighted as target for anti-cancer therapy to improve morbidity and mortality of PCa patients.
Prostate cancer (PCa) is the second leading cause of cancer-related mortality in American men. Androgen ablation therapies are initially effective in ~90% of PCa patients. Unfortunately, these therapies offer only a temporary relief and the disease eventually recurs with a lethal outcome. PCa that relapsed after hormonal therapies is the major cause of disease lethality and is referred to as castration-resistant PC (CRPC). To make progress in CRPC treatment, we must develop evidence-based strategies for choosing therapy interventions. A better understanding of mechanisms that control androgen receptor (AR) activation and allow CRPC to circumvent hormonal ablation therapies is critically important for improving disease outcome. This pilot proposal aims to answer two questions: First, do histone variants contribute to CRPC etiology, and second, is interaction between histone chaperone Daxx and AR play a role in this process. If Daxx/AR were shown to have a role in regulating CRPC progression, this complex would be further highlighted as target for anti-cancer therapy to improve morbidity and mortality of PCa patients. Altogether, this work supposes to rationally identify novel targeted and combinatorial therapeutic regimens for treatment of CRPC.
| Rivera-Rodriguez, Angelie; Chiu-Lam, Andreina; Morozov, Viacheslav M et al. (2018) Magnetic nanoparticle hyperthermia potentiates paclitaxel activity in sensitive and resistant breast cancer cells. Int J Nanomedicine 13:4771-4779 |
| Morozov, Viacheslav M; Li, Ying; Clowers, Matthew M et al. (2017) Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer. Oncotarget 8:62131-62142 |
| Morozov, Viacheslav M; Giovinazzi, Serena; Ishov, Alexander M (2017) CENP-B protects centromere chromatin integrity by facilitating histone deposition via the H3.3-specific chaperone Daxx. Epigenetics Chromatin 10:63 |
