Friday, May 10, 2024
5/10/2024
Project Summary GATA2 is emerging as a key therapeutic target for prostate cancer (PCa) since it plays essential roles in promoting PCa androgen receptor (AR) expression/activation, tumor growth, and therapy resistance. Although it is challenging to directly inhibit GATA2 transcriptional activity, enhancing GATA2 protein degradation represents a promising therapeutic strategy, especially for the lethal castration-resistant PCa (CRPC) and taxane-resistant CRPC (TxR-CRPC). The underlying molecular mechanism for GATA2 degradation in PCa is unknown. We identified COP1, an E3 ubiquitin ligase, playing essential roles in promoting GATA2 degradation in PCa. Our preliminary data suggest that COP1 greatly inhibits AR activation and AR+ PCa cell/xenografts growth. Besides, COP1 re-sensitizes both AR+ and AR– TxR-CRPC to docetaxel, potentially by reversing the GATA2 overexpression that is acquired during the development of taxane-resistance. Finally, COP1 expression negatively correlates with AR expression/ activation in public PCa datasets. Based on these exciting data, we hypothesize that 1) COP1 is the bona fide E3 ligase for GATA2 in PCa. By promoting GATA2 degradation, 2) COP1 inhibits AR signaling, AR+ PCa growth/castration-resistance, and 3) COP1 represses taxane chemoresistance of both AR+ and AR– PCa. In Aim 1, we will investigate how COP1 regulates GATA2 degradation in PCa. We will address COP1-mediated GATA2 ubiquitination/degradation, COP1-GATA2 interaction, and the associated molecular mechanisms in PCa/CRPC/TxR-CRPC. In Aim 2, we will investigate how COP1 regulates AR expression/activation and AR+ PCa/CRPC growth. We will also address the GATA2- dependent vs. GATA2-independent function of COP1 in regulating AR signaling and AR+ PCa/CRPC growth and determine how COP1 protein levels correlate with GATA2/AR levels in human PCa tissues. In Aim 3, we will investigate how COP1 affects the taxane resistance in PCa. We will address how COP1 regulates AR– and AR+ TxR-CRPC and assess the GATA2-dependent vs. GATA2-independent function of COP1 in regulating TxR- CRPC growth and taxane resistance. Accomplishing these aims will, for the first time, establish COP1 as the highly sought-after E3 ubiquitin ligase for GATA2 and demonstrate COP1 as a key tumor repressor to potently suppress PCa, especially the lethal CRPC and TxR-CRPC. These will significantly advance our understanding of the molecular mechanisms regulating PCa AR expression/activation, tumor growth, castration resistance, and taxane chemoresistance. Hence, our study is both highly significant and novel.
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