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.

项目概要 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) 表达/激活、肿瘤生长和治疗耐药性。直接抑制GATA2转录活性、增强GATA2蛋白降解具有挑战性代表了一种有前途的治疗策略，特别是对于致命的去势抵抗性前列腺癌（CRPC）和 PCa 中 GATA2 降解的基本分子机制是紫杉烷抗性 CRPC (TxR-CRPC)。我们鉴定出 COP1，一种 E3 泛素连接酶，在促进 GATA2 降解中发挥重要作用。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。此外，COP1 可能通过逆转 AR+ 和 AR-TxR-CRPC 对多西紫杉醇重新敏感。 GATA2 过度表达是在紫杉烷抗性发展过程中获得的，最后是 COP1 表达。基于这些令人兴奋的数据，我们与公共 PCa 数据集中的 AR 表达/激活呈负相关。坚持认为 1) COP1 是 PCa 中 GATA2 的真正 E3 连接酶，通过促进 GATA2 降解，2) COP1 抑制 AR 信号传导、AR+ PCa 生长/去势抵抗，以及 3) COP1 抑制紫杉烷 AR+ 和 AR- PCa 的化学耐药性在目标 1 中，我们将研究 COP1 如何调节 GATA2。我们将解决 COP1 介导的 GATA2 泛素化/降解，COP1-GATA2 在目标 2 中，我们将研究 PCa/CRPC/TxR-CRPC 中的相互作用以及相关分子机制。 COP1 如何调节 AR 表达/激活和 AR+ PCa/CRPC 生长我们还将讨论 GATA2-。 COP1 在调节 AR 信号传导和 AR+ PCa/CRPC 生长中的依赖性与非 GATA2 功能确定人类 PCa 组织中 COP1 蛋白水平与 GATA2/AR 水平的相关性在目标 3 中，我们将。研究 COP1 如何影响 PCa 中的紫杉烷耐药性我们将讨论 COP1 如何调节 AR– 和 AR+。 TxR-CRPC 并评估 COP1 在调节 TxR-中的 GATA2 依赖性与 GATA2 独立功能 CRPC 的增长和紫杉烷耐药性的实现将首次将 COP1 确立为主要目标。备受追捧的 GATA2 的 E3 泛素连接酶，并证明 COP1 作为有效的关键肿瘤抑制因子抑制 PCa，特别是致命的 CRPC 和 TxR-CRPC，这些将显着增进我们的理解。调节 PCa AR 表达/激活、肿瘤生长、去势抵抗和因此，我们的研究既非常重要又新颖。