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：
10463748
负责人：
CHARLES ROBERTS
金额：
$ 39.09万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463748
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?

项目摘要/摘要：癌症基因组测序研究现已表明，编码九个不同亚基的基因 SWI/SNF染色质重塑络合物经常在各种各样的人类癌症中突变。这些包括大脑癌，卵巢，乳房，肾脏，肺，胰腺，子宫，膀胱，胃，结肠，肝脏，皮肤和皮肤和皮肤血。总的来说，超过20％的人类癌症包含SWI/SNF突变，使SWI/SNF产生复合物是癌症中最常见的染色质/表观遗传调节剂。在当前资金期间循环我们在阐明SWI/SNF复合物的功能方面取得了显着的进步。但是，主要问题随后出现了。 SWI/SNF复合物由核心亚基和变体亚基组成，后者仅存在于复合物的子类中。现在已经很清楚，频繁变异亚基都是所有变体亚基，包括arid1a，smarca4和pbrm1，每个突变是与独特的癌症相关。但是，这些的机械和功能贡献对SWI/SNF功能的变体亚基和子类知之甚少。我们假设肿瘤发生发生并不是由于SWI/SNF复合功能的广泛丧失，而是由于残留的异常功能 SWI/SNF复合体。我们进一步假设，变体肿瘤抑制剂亚基的损失改变了 SWI/SNF的组成，靶向和染色质重塑活性，从而损害分化和促进肿瘤发生。使用我们的基因工程主细胞，细胞系和小鼠，我们将解决三个目的：目标1：SWI/SNF复合物的互斥亚基，SMARCA4/BRG1如何和smarca2/brm，功能不同，smarca2合成致死性的机理基础是什么在Smarca4突变癌中？ AIM 2：SWI/SNF复合物的PBRM1-Containig PBAF子类如何相对于成分，靶向染色质重塑，与含有ARID1A/B的BAF子类不同活动，增强子调节和谱系规范的控制？目标3：我们新发现的BRD9-如何包含子类的组成和功能与其他SWI/SNF子类别不同，并且BRD9可以被利用为治疗靶标？