COP1 Regulation of Prostate Cancer Biology
Abstract
Castration-resistant prostate cancer (CRPC) is lethal. Interestingly, most CRPCs remain dependent on Androgen Receptor (AR) activity, and inhibiting AR remains a major therapeutic approach for most CRPCs. A protein named GATA2 plays essential roles in governing AR expression/ activation to promote PCa and castration resistance. Clinically, high GATA2 expression in human PCa correlates with advanced stages, worse prognosis, and therapy resistance. Thus, GATA2 forms a central node of PCa and lethal CRPC. Unfortunately, previous efforts have not yet identified true GATA2 inhibitors for therapy. GATA2 protein is unstable, and enhancing GATA2 protein degradation is a promising therapeutic avenue. These highlight the significance of understanding the molecular mechanisms regulating GATA2 protein stability in PCa/CRPC. The E3 ubiquitin ligases are enzymes essential for protein degradation. So far, the E3 ligase for GATA2 degradation in PCa/CRPC is unknown. Our current study will establish the novel concept that COP1 is the first bona fide E3 ubiquitin ligase for GATA2 degradation in PCa/CRPC; this was originally discovered by the Principal Investigator and has never been reported. The successful completion of our study will fully characterize the striking activities of COP1 on suppressing PCa cell/xenograft growth and castration resistance. Our study will establish GATA2 as the missing major functionally significant substrate of COP1 in human PCa and define the COP1-GATA2 axis as a direct novel mechanism for COP1 regulating AR expression/activation, PCa growth, and castration-resistance. Mechanistically, we will define how COP1 utilizes different mechanisms for binding and thus degradation of GATA2 vs. other canonical substrates and assess the roles of GATA2 in mediating COP1 biology in PCa/CRPC. This grant will address the FY22 PCRP Overarching Challenge of Define the biology of prostate cancer progression to lethal prostate cancer to reduce death. How the COP1-GATA2 axis is regulated in PCa is unknown. Our pioneering studies revealed that MAPK4, a protein not well studied, promotes tumor progression and therapy resistance via non-canonical activation of a key tumor-promoting signaling pathway (Wang et al., J Clin Invest, 2019; Shen et al., J Clin Invest, 2021; Cai et al., Sci Adv, 2021; Wang et al., Nat Commun, 2022). We also discovered that MAPK4 enhances GATA2/AR signaling to promote PCa growth and castration resistance (Shen et al., J Clin Invest, 2021), and this is at least partially mediated by MAPK4 blocking COP1-GATA2 binding and thus COP1-mediated GATA2 degradation. Therefore, therapeutically enhancing COP1 degradation of GATA2 can be achieved by (1) MAPK4 inhibitors (we have identified two leading compounds to inhibit MAPK4) and (2) developing molecular glue, a new class of small molecules, to further enhance COP1-GATA2 binding and/or glue GATA2 and COP1 proteins together in the presence of COP1-GATA2 binding blocker(s), e.g., MAPK4. Therefore, the short-term impact of our study includes the discovery of COP1 promoting GATA2 degradation as a direct and novel mechanism for repressing AR expression/activation, inhibiting PCa growth, and sensitizing PCa to androgen-deprivation therapy. These will identify/establish targeting our newly discovered COP1-GATA2 axis as a novel and effective therapeutic avenue for PCa and lethal CRPC. The long-term impact includes developing MAPK4 inhibitors (we have already identified two leading compounds) and/or molecular glue(s) to activate our newly discovered COP1-GATA2 axis, which will produce novel and effective therapies for lethal CRPC. All in all, by pioneering the COP1-GATA2 axis and COP1 biology in repressing AR expression/activation, PCa growth, and castration resistance, our study is original, highly innovative, and will have a high impact on both the PCa research field and patient care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310095
Entities
People
- Feng Yang
Organizations
- Baylor College of Medicine
- United States Army