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

COP1 对 AR 信号传导和前列腺癌生长及治疗耐药的监管

基本信息

批准号：
10660204
负责人：
Feng Yang
金额：
$ 48.53万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660204
关键词：
Address Affect Androgen Receptor Applications Grants Automobile Driving Binding Cancer Biology Castration Cellular biology Chemoresistance Clinic Consensus Data Data Set Development Disease Progression GATA2 transcription factor Genetic Transcription Goals Growth Human In Vitro Investments Link MAP Kinase Gene MAPK4 gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Patients Play Proteins Proto-Oncogene Proteins c-akt RNA Splicing Receptor Activation Receptor Signaling Regulation Repression Resistance Role Signal Transduction System Testing Therapeutic Time Tissues Ubiquitination Variant Work Xenograft procedure abiraterone androgen deprivation therapy androgen independent prostate cancer cancer therapy castration resistant prostate cancer chemotherapy docetaxel enzalutamide in vivo inhibitor inhibitor therapy mutant novel novel therapeutic intervention overexpression patient derived xenograft model prostate cancer cell protein degradation receptor expression taxane therapeutic target therapy resistant tumor tumor growth ubiquitin-protein ligase

项目摘要

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.

项目摘要 GATA2正在成为前列腺癌（PCA）的关键治疗靶标，因为它在促进PCA雄激素受体（AR）表达/激活，肿瘤生长和耐药性。虽然直接抑制GATA2转录活性，增强GATA2蛋白降解是有挑战的代表了一种有前途的治疗策略，特别是对于耐致命的castration PCA（CRPC）和抗紫杉烷CRPC（TXR-CRPC）。 PCA中GATA2降解的基本分子机制为未知。我们确定了E3泛素连接酶COP1，在促进GATA2降解中起着重要作用在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/异种移植物生长。此外，COP1将AR+和AR – TXR-CRPC重新敏感为多西他赛，可能是通过逆转 GATA2过表达在开发紫杉烷耐药过程中获得。最后，COP1表达与公共PCA数据集中的AR表达/激活相关。基于这些令人兴奋的数据，我们假设1）COP1是PCA中GATA2的真正的E3连接酶。通过促进GATA2降解，2） COP1抑制AR信号传导，AR+ PCA生长/castration抗性，3）COP1反映紫杉烷 AR+和AR -PCA的化学抗性。在AIM 1中，我们将研究COP1如何调节GATA2 PCA降解。我们将解决COP1介导的GATA2泛素化/降解，COP1-GATA22 相互作用以及PCA/CRPC/TXR-CRPC中的相关分子机制。在AIM 2中，我们将调查 COP1如何调节AR表达/激活和AR+ PCA/CRPC生长。我们还将解决GATA2- COP1在调节AR信号传导和AR+ PCA/CRPC生长方面的依赖与GATA2无关的功能以及确定COP1蛋白水平与人PCA组织中的GATA2/AR水平相关。在AIM 3中，我们将研究COP1如何影响PCA中的紫杉烷耐药性。我们将解决COP1如何调节AR – AR+ TXR-CRPC并评估COP1在调节TXR-中的GATA2依赖性与GATA2独立的功能 CRPC生长和紫杉烷耐药性。实现这些目标将首次确定COP1 GATA2的E3泛素连接酶非常令人沮丧，并将COP1作为关键肿瘤复制品可能抑制PCA，尤其是致命的CRPC和TXR-CRPC。这些将大大提高我们的理解调查PCA AR表达/激活，肿瘤生长，castration抗性和的分子机制紫杉烷化学抗性。因此，我们的研究既重要又新颖。