Collaborative genomic alterations and transcriptional control in prostate cancer

项目摘要/摘要 前列腺癌的分子特征揭示了不同的亚型，但生物学意义和 这些翻译的影响仍不清楚。我们最近定义了前列腺癌的一个独特的分子亚类 以泛素连接酶SPOP突变和缺失为特征的癌症 核小体重构体CHD1.然而，SPOP突变和CHD1缺失的机制 合作推动前列腺癌的发生仍不清楚。 这项提案的总体目标是定义SPOP突变和CHD1 缺失协同作用推动了前列腺癌的发生。使用新的模型，我们的初步数据表明 SPOP突变改变了与SPOP功能和物理相关的蛋白质的表达 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，我们还发现，CHD1的缺失从根本上改变了AR-cstrome的程序 和转录程序，从抑制生长的AR程序分流 一个致癌项目。这些结果表明，SPOP的突变可以稳定关键底物 与AR活动有关，且CHD1缺失与AR- 促进癌基因转录和前列腺癌发生的转录复合体。这个项目将 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CHD1缺失在前列腺癌发病中的协同作用，2)明确 由SPOP突变介导的AR转录复合体的改变，以及3)决定 SPOP突变引起的改变对与CHD1的丢失和重新编程至关重要 AR转录组。为了实现这一点，我们将利用独特的、生物和临床相关的模型 系统，蛋白质组和转录组发现的创新方法，以及来自人类前列腺的数据 癌症样本。该项目将确定SPOP突变体/CHD1缺失的关键转录过程 前列腺癌和前列腺癌亚型之间更广泛的适用性，并为 针对这一亚类的精确临床试验。

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.