The tumor suppressive role of PBRM1, the bromodomain-containing subunit of the PBAF chromatin remodeling complex

PBRM1（PBAF 染色质重塑复合物的含溴结构域亚基）的肿瘤抑制作用

基本信息

批准号：
9908057
负责人：
Emily Carla Dykhuizen
金额：
$ 34.92万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908057
关键词：
Adult Affinity Animal Model Belief Binding Binding Sites Biological Assay Biology Bromodomain Cell Adhesion Cell Adhesion Molecules Cell Line Cell Polarity Cells Cellular Assay Cellular Morphology Cessation of life Chromatin Chromatin Remodeling Factor Chromatin Structure Clear cell renal cell carcinoma Clinic Code Complex Conventional (Clear Cell) Renal Cell Carcinoma Data Disease Disease-Free Survival Enzymes Epigenetic Process Epithelial Epithelial Cells Epithelium Event Fostering Gene Activation Gene Expression Regulation Genes Genetic Transcription Genomic Segment Genomics Goals Health Histone Acetylation Histones Human Investigation Kidney Lysine Maintenance Malignant Neoplasms Massive Parallel Sequencing Mediating Mesenchymal Minor Missense Mutation Mission Modeling Molecular Mutate Mutation Nucleosomes Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiological Protein Binding Domain Proteins Public Health Regulation Renal carcinoma Research Resistance Role SMARCA4 gene Sampling Signal Transduction Site Survival Rate Testing Therapeutic Therapeutic Intervention Therapeutic Uses Transcriptional Activation Transcriptional Regulation Treatment Efficacy Tumor Suppression Tumor Suppressor Proteins Work base chemotherapy chromatin remodeling genome-wide improved improved outcome in vivo inhibitor/antagonist innovation knock-down mutational status new therapeutic target patient response polybromo recruit response targeted treatment three dimensional cell culture transcription factor transcriptome sequencing translational impact tumor tumorigenesis

项目摘要

Project Summary Metastatic clear cell renal cell carcinoma (ccRCC) has low disease-free survival and limited therapeutic options. The only treatments for ccRCC have been elucidated as a result of mechanistic understanding of tumor suppression by VHL (von Hippel-Lindau), the most commonly mutated gene in ccRCC. After VHL, the second most commonly mutated gene in ccRCC patients is Polybromo-1 (PBRM1), a subunit of the SWI/SNF (or BAF for BRG1/BRM associated factors) chromatin remodeling complex, subunits of which are mutated in 20% of human cancers. PBRM1 is characterized by six sequential bromodomains proposed to bind acetylated lysines and is a subunit in a minor BAF subcomplex called PBAF (for Polybromo-1 BAF). The overall goal of this proposal is to determine the mechanism of PBRM1-mediated chromatin targeting of the PBAF complex and how that relates to downstream transcriptional regulation of genes important for tumor suppression in ccRCC. Based on our preliminary data, we hypothesize that several of the six bromodomains of PBRM1 are required for multivalent targeting of the PBAF complex to multiple histone acetylation sites located at genomic regions important for the regulation of genes involved in cell adhesion and epithelial maintenance. In the proposed study we plan to 1) Use cellular assays and animal models to confirm and characterize PBRM1 as a tumor suppressor involved in the regulation of cell adhesion, 2) Define how PBRM1 status predicts therapeutic efficacy of established and proposed ccRCC drugs, 3) Identify genomic binding sites for PBRM1 in ccRCC and the transcriptional regulation by PBAF-mediated chromatin remodeling, and 4) Define the histone acetylation marks responsible for specific recruitment of PBRM1 and PBAF. The proposed study will greatly increase our understanding of the mechanisms involved in renal tumorigenesis and expand our understanding of the tumor suppressive mechanisms of BAF-mediated chromatin remodeling. It is our belief that this study will provide direct evidence of novel therapeutic targets for treating renal cancer.

项目摘要转移性透明细胞肾细胞癌（CCRCC）的无病生存率低，治疗选择有限。由于对肿瘤的机械理解，CCRC的唯一治疗方法已被阐明 VHL（von Hippel-Lindau）抑制，CCRCC中最常见的基因。在VHL之后，第二 CCRCC患者中最常见的突变基因是polybromo-1（PBRM1），SWI/SNF的亚基（或BAF 对于BRG1/BRM相关因素）染色质重塑复合物，其亚基在20％中被突变人类癌。 PBRM1的特征是提出了六个顺序的溴结构域，该溴脱域提出结合乙酰化赖氨酸并且是称为PBAF的小BAF子复合物（用于PolyBromo-1 BAF）的亚基。总体目标建议是确定PBRM1介导的PBAF复合物的染色质靶向和这与CCRCC中肿瘤抑制重要的基因下游转录调节有关。根据我们的初步数据，我们假设需要PBRM1的六个溴化群中的几个用于将PBAF复合物的多价靶向位于基因组区域的多个组蛋白乙酰化位点对于调节细胞粘附和上皮维持的基因很重要。在提议中研究我们计划1）使用细胞测定和动物模型来确认并将PBRM1描述为肿瘤与细胞粘附调节有关的抑制剂，2）定义PBRM1状态如何预测治疗已建立和提出的CCRCC药物的功效，3）识别CCRCC和 PBAF介导的染色质重塑的转录调节，4）定义组蛋白乙酰化负责特定募集PBRM1和PBAF的标记。拟议的研究将大大增加我们的了解肾脏肿瘤发生的机制并扩展我们对肿瘤的理解 BAF介导的染色质重塑的抑制性机制。我们相信这项研究将提供新型治疗肾癌治疗靶标的直接证据。