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

项目摘要 GATA2正在成为前列腺癌(PCA)的关键治疗靶点，因为它在 促进PCA雄激素受体(AR)的表达/激活、肿瘤生长和治疗耐药。虽然 直接抑制GATA2转录活性，促进GATA2蛋白降解是一项具有挑战性的工作 代表了一种很有前途的治疗策略，特别是对于致命的抗阉割PCa(CRPC)和 紫杉烷耐药CRPC(TxR-CRPC)。前列腺癌中GATA2降解的潜在分子机制是 未知。我们确定了COP1，一种E3泛素连接酶，在促进GATA2降解方面发挥着重要作用 在PCA中。我们的初步数据表明，COP1极大地抑制AR激活和AR PCA细胞/异种移植 成长。此外，COP1使AR和AR-TxR-CRPC对多西紫杉醇重新增敏，可能是通过逆转 在紫杉烷耐药性形成过程中获得的GATA2过表达。最后，COP1表达式 在公共PCA数据集中，AR表达/激活与AR负相关。基于这些令人兴奋的数据，我们 假设1)COP1是前列腺癌中GATA2真正的E3连接酶。通过促进GATA2降级，2) COP1抑制AR信号转导，AR-PCA生长/去势抵抗，3)COP1抑制紫杉烷 AR和AR-PCa的化疗耐药。在目标1中，我们将调查COP1如何调节GATA2 主成分分析中的降解。我们将讨论COP1介导的GATA2泛素化/降解，COP1-GATA2 PCA/CRPC/TxR-CRPC的相互作用及其相关的分子机制。在目标2中，我们将调查 COP1如何调控AR表达/激活和AR PCA/CRPC生长我们还将讨论GATA2- COP1在调节AR信号和AR PCA/CRPC生长中的依赖与GATA2非依赖性功能 确定人类前列腺癌组织中COP1蛋白水平与GATA2/AR水平之间的相关性。在《目标3》中，我们将 研究COP1如何影响前列腺癌中紫杉烷的耐药性。我们将讨论COP1如何调节AR-和AR TxR-CRPC，并评估COP1在调节TxR-CRPC中的GATA2依赖功能与GATA2非依赖功能 CRPC生长和紫杉烷耐药性。实现这些目标将首次使《公约》缔约方会议成为 GATA2的E3泛素连接酶备受追捧，并证明COP1是一种关键的肿瘤抑制因子 抑制前列腺癌，尤其是致死性的CRPC和TxR-CRPC。这些将极大地促进我们的理解 调控Pca AR表达/激活、肿瘤生长、去势抵抗和 紫杉烷耐药。因此，我们的研究既具有重要意义，又具有新颖性。

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.