Collaborative genomic alterations and transcriptional control in prostate cancer

前列腺癌中的协同基因组改变和转录控制

• 批准号: 10549377
• 负责人: Christopher E Barbieri
• 金额: $ 53.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549377
• 关键词: Affect; Androgen Receptor; Binding; Biological; Biological Models; Biology; CHD1 gene; Cells; Chromatin; Clinical Course of Disease; Clinical Trials; Collaborations; Complex; DNA Sequence Alteration; Data; Diagnosis; Disease; EP300 gene; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genomic approach; Growth; Histologic; In Vitro; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Missense Mutation; Modeling; Molecular; Mus; Mutation; Neoplasms; Nucleosomes; Oncogenic; Pathogenesis; Patients; Phenotype; Play; Prostate; Proteins; Proteome; Proteomics; Recurrence; Role; Sampling; Shapes; Signal Transduction; Specificity; Testing; Therapeutic Intervention; Transcription Process; Transcriptional Regulation; cancer subtypes; clinically relevant; cohort; functional genomics; genome-wide; human data; human disease; in vivo; innovation; insight; men; mutant; new therapeutic target; novel; novel diagnostics; novel therapeutic intervention; programs; prostate carcinogenesis; protein expression; stoichiometry; targeted treatment; therapeutic biomarker; therapeutic target; transcriptome; transcriptomics; translational impact; ubiquitin ligase

PROJECT SUMMARY / ABSTRACT Molecular characterization of prostate cancer has revealed distinct subtypes, but the biologic implications and translational impact of these are still unclear. We recently defined a distinct molecular subclass of prostate cancer characterized by the combination of mutations in the ubiquitin ligase SPOP, and deletion of the nucleosome remodeler CHD1. However, the mechanisms by which SPOP mutation and CHD1 deletion collaborate to drive prostate tumorigenesis remain unknown. The overall objective of this proposal is to define the mechanisms by which SPOP mutation and CHD1 deletion collaborate to drive prostate tumorigenesis. Using novel models, our preliminary data demonstrate that SPOP mutation alters expression of proteins that are functionally and physically associated with the androgen receptor (AR), a critical driver for prostate cancer and key therapeutic target, and alters AR-driven gene expression. Furthermore, we have found that CHD1 deletion fundamentally reprograms the AR-cistrome and transcriptional program in prostate cells, diverting away from a growth suppressive AR program and towards an oncogenic program. These results suggest that mutation of SPOP stabilizes key substrates involved in AR activity, and that CHD1 deletion specifically collaborates with these changes in the AR- transcriptional complex to promote oncogenic transcription and prostate tumorigenesis. This project will elucidate the molecular details underlying these phenomena through the following Aims: 1) establishing the collaborative impact of SPOP mutation and CHD1 deletion on the pathogenesis of prostate cancer, 2) defining the alterations to the AR-transcriptional complex mediated by SPOP mutation, and 3) determining the alterations induced by SPOP mutation that are critical for collaboration with CHD1 loss and reprograming of the AR transcriptome. To accomplish this, we will leverage unique, biologically and clinically relevant model systems, innovative approaches to proteomic and transcriptomic discovery, and data from human prostate cancer samples. This project will define the critical transcriptional processes in SPOP mutant / CHD1 deleted prostate cancer and the broader applicability across prostate cancer subtypes, and provide the foundation for precision clinical trials targeting this subclass.

项目总结/摘要 前列腺癌的分子特征揭示了不同的亚型，但其生物学意义和 这些翻译的影响尚不清楚。我们最近定义了前列腺的一个独特的分子亚类 特征为泛素连接酶SPOP突变和缺失的组合的癌症， 核小体重塑因子CHD 1。然而，SPOP突变和CHD 1缺失的机制 协同驱动前列腺肿瘤发生仍然是未知的。 本提案的总体目标是确定SPOP突变和CHD 1 缺失协同驱动前列腺肿瘤发生。使用新的模型，我们的初步数据表明， SPOP突变改变了与肿瘤相关的功能和物理蛋白质的表达， 雄激素受体（AR），前列腺癌的关键驱动因素和关键治疗靶点，并改变AR驱动的 基因表达。此外，我们已经发现CHD 1缺失从根本上重新编程AR-顺反组， 和转录程序，从生长抑制AR程序转移， 一个致癌项目这些结果表明，SPOP的突变稳定了关键底物 参与AR活动，并且CHD 1缺失特异性地与AR中的这些变化协同作用。 转录复合物促进致癌转录和前列腺肿瘤发生。该项目将 通过以下目的阐明这些现象背后的分子细节：1）建立 SPOP突变和CHD 1缺失对前列腺癌发病机制的协同影响，2）定义 由SPOP突变介导的AR-转录复合物的改变，以及3）确定 SPOP突变诱导的改变，对于与CHD 1丢失和重编程的协作至关重要。 AR转录组。为了实现这一目标，我们将利用独特的生物学和临床相关模型 系统，蛋白质组学和转录组学发现的创新方法，以及来自人类前列腺的数据 癌症样本本项目将定义SPOP突变体/CHD 1缺失的关键转录过程 前列腺癌和前列腺癌亚型的更广泛的适用性，并提供了基础， 针对该亚类的精准临床试验。