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Role of the SWI/SNF complex in tumor suppression

SWI/SNF 复合物在肿瘤抑制中的作用

基本信息

批准号：
10248410
负责人：
CHARLES ROBERTS
金额：
$ 39.9万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248410
关键词：
ARID1A gene ATP Hydrolysis ATP phosphohydrolase Address Biological Bladder Blood Breast Bromodomain Cancer Etiology Cell Line Cells Chromatin Chromatin Remodeling Factor Colon Colon Carcinoma Complex Data Dependence Disease EZH2 gene Enhancers Epigenetic Process Frequencies Funding Gene Expression Gene Mutation Genes Genetic Engineering Genomics Goals Grant Growth Human Impairment Kidney Laboratory Research Liver Lung Maintenance Malignant Neoplasms Malignant neoplasm of brain Mus Mutate Mutation Nucleosomes Oncogenes Ovary Pancreas Phase II Clinical Trials Positioning Attribute Proteins Regulation Reporting Residual state Role SMARCA2 gene SMARCA4 gene SMARCB1 gene SWI/SNF Family Complex Skin Stomach Testing Therapeutic Transcriptional Regulation Tumor Suppression Tumor Suppressor Proteins Uterus Variant cancer genome chromatin remodeling comparative experimental study genome sequencing human disease human model mutant mutant mouse model new therapeutic target novel programs rare cancer targeted treatment therapeutic target therapeutically effective tumorigenesis

项目摘要

Project Summary/Abstract: Cancer genome sequencing studies have now revealed that genes that encode nine different subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in a wide variety of human cancers. These include cancers of brain, ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver, skin and blood. Collectively, over twenty percent of all human cancers contain a SWI/SNF mutation making SWI/SNF complexes the most frequently mutated chromatin/epigenetic regulator in cancer. During the current funding cycle we have made notable progress in elucidating the functions of SWI/SNF complexes. However, major questions have subsequently emerged. SWI/SNF complexes consist of both core subunits and variant subunits, with the latter present in only sub-classes of complexes. It has now become clear that the frequently mutated subunits are all variant subunits including ARID1A, SMARCA4 and PBRM1 and that mutation of each is associated with a distinct cancer spectrum. However, the mechanistic and functional contributions of these variant subunits and sub-classes to SWI/SNF function is poorly understood. We hypothesize that oncogenesis occurs not due to broad loss of SWI/SNF complex function but rather due to aberrant function of residual SWI/SNF complexes. We further hypothesize that loss of the variant tumor-suppressor subunits alters the composition, targeting and chromatin remodeling activity of SWI/SNF thus impairing differentiation and promoting oncogenesis. Using our genetically engineered primary cells, cell lines and mice, we will address three aims: Aim 1: How do the mutually exclusive ATPase subunits of SWI/SNF complexes, SMARCA4/BRG1 and SMARCA2/BRM, differ in function and what is the mechanistic basis for the synthetic lethality of SMARCA2 in SMARCA4 mutant cancers? Aim 2: How does the PBRM1-containig PBAF sub-class of SWI/SNF complexes differ from the ARID1A/B-containing BAF sub-class with respect to composition, targeting, chromatin remodeling activity, enhancer regulation and control of lineage specification? Aim 3: How does our newly discovered BRD9- containing sub-class differ in composition and function from other SWI/SNF sub-classes, and can BRD9 be exploited as a therapeutic target?

项目总结/文摘: