COP1 REGULATION OF AR SIGNALING AND PROSTATE CANCER GROWTH AND THERAPY RESISTANCE

项目摘要 GATA 2正在成为前列腺癌（PCa）的关键治疗靶点，因为它在前列腺癌的治疗中发挥重要作用。 促进PCa雄激素受体（AR）表达/激活、肿瘤生长和治疗耐药性。虽然 直接抑制GATA 2转录活性，增强GATA 2蛋白降解， 代表了一种有前途的治疗策略，特别是对于致死性去势抵抗性PCa（CRPC）， 紫杉烷耐药CRPC（TxR-CRPC）。PCa中GATA 2降解的潜在分子机制是 未知我们鉴定了COP 1，一种E3泛素连接酶，在促进GATA 2降解中起重要作用 在PCa。我们的初步数据表明，COP 1极大地抑制AR激活和AR+ PCa细胞/异种移植物 增长此外，COP 1可能通过逆转AR+和AR-TxR-CRPC对多西他赛的敏感性， GATA 2过度表达是在紫杉烷耐药的发展过程中获得的。最后，COP 1表达 与公共PCa数据集中的AR表达/激活负相关。基于这些令人兴奋的数据，我们 假设1）COP 1是PCa中GATA 2的真正E3连接酶。通过促进GATA 2降解，2） COP 1抑制AR信号传导、AR+ PCa生长/去势抵抗，以及3）COP 1抑制紫杉烷 AR+和AR-PCa两者的化学抗性。在目标1中，我们将研究COP 1如何调节GATA 2 PCa降解。我们将讨论COP 1介导的GATA 2泛素化/降解，COP 1-GATA 2 PCa/CRPC/TxR-CRPC中的相互作用以及相关的分子机制。在目标2中，我们将研究 COP 1如何调节AR表达/活化和AR+ PCa/CRPC生长。我们还将讨论GATA 2- COP 1在调节AR信号传导和AR+ PCa/CRPC生长中的依赖性与非GATA 2依赖性功能， 确定COP 1蛋白水平如何与人PCa组织中的GATA 2/AR水平相关。在目标3中，我们 研究COP 1如何影响PCa的紫杉烷耐药性。我们将讨论COP 1如何调节AR-和AR+ TxR-CRPC，并评估COP 1在调节TxR-CRPC中的GATA 2依赖性与GATA 2非依赖性功能。 CRPC生长和紫杉烷耐药性。实现这些目标将首次将第一届缔约方会议确立为 高度抢手的E3泛素连接酶GATA 2，并证明COP 1作为一个关键的肿瘤抑制剂， 抑制PCa，尤其是致死性CRPC和TxR-CRPC。这将大大促进我们对 调节PCa AR表达/活化、肿瘤生长、去势抵抗的分子机制， 紫杉烷耐药性因此，本研究具有重要意义和新颖性。

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.