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Analysis of the role of the SWI/SNF complex in tumor suppression

SWI/SNF复合物抑制肿瘤的作用分析

基本信息

批准号：
8579030
负责人：
CHARLES ROBERTS
金额：
$ 35.93万
依托单位：
DANA-FARBER CANCER INST
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8579030
关键词：
ATP Hydrolysis Affect Bladder Breast Cancer Etiology Cancer cell line Cell Line Chromatin Chromatin Remodeling Factor Chromatin Structure Colon Colorectal Cancer Complex DNA DNA Binding Data Development EZH2 gene Epigenetic Process Event Frequencies Gene Expression Gene Mutation Generations Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Histone H3 Human Impairment Individual Kidney Knockout Mice Laboratories Laboratory Research Liver Lung Lysine Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Modeling Molecular Mus Mutate Mutation Non-Small-Cell Lung Carcinoma Nucleosomes Ovarian Ovary Pancreas Pancreatic carcinoma Pathway interactions Polycomb Positioning Attribute Publications Recurrence Renal carcinoma Residual state Rhabdoid Tumor Role SMARCA4 gene SMARCB1 gene Site-Directed Mutagenesis Skin Stomach Testing Therapeutic Translations Tumor Suppression Tumor Suppressor Proteins Uterus base cancer cell cancer genome chromatin remodeling clinically relevant driving force exome sequencing genome sequencing histone modification human disease in vivo inhibitor/antagonist insight interest malignant breast neoplasm malignant stomach neoplasm melanoma mouse model mutant novel programs public health relevance research study therapeutic target tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Emerging data implicate the SWI/SNF chromatin remodeling complex as a major tumor suppressor. Over the past [two years], numerous cancer genome sequencing studies have revealed that at least six subunits of the complex are specifically inactivated at high frequency in a variety of human cancers including those of ovary, breast, kidney, lung, pancreas, uterus, bladder, stomach, colon, liver [and skin]. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure. My laboratory has demonstrated a potent and bona fide tumor suppressor role for one of the subunits through generation of a knockout mouse model. Providing some insight into mechanism, we have recently established the existence of epigenetic antagonism between SWI/SNF and Polycomb complexes. However, the contributions of the SWI/SNF complex to chromatin structure in vivo and the reasons why each subunit is associated with distinct cancer spectra remain poorly understood. Given the unique chromatin targeting and modification domains found in each subunit, we hypothesize that oncogenesis occurs due to differential mistargeting of residual SWI/SNF complexes and impairment of their chromatin remodeling activity. We further hypothesize that SWI/SNF subunit mutations cause disruption of lineage-specific gene expression programs arising from imbalanced epigenetic antagonism with the Polycomb PRC2 complex. Via the following specific aims, our goals are to determine how the subunits of the SWI/SNF complex contribute to chromatin structure, to establish the mechanism by which mutation of the tumor suppressor subunits drives cancer formation, to determine the extent of epigenetic antagonism between the tumor suppressor subunits and the PRC2 complex, and to identify novel and effective therapeutic targets for SWI/SNF mutant cancers: Aim 1: How does loss of individual SWI/SNF tumor suppressor subunits affect the DNA binding, chromatin remodeling activity, and integrity of the SWI/SNF complex, and how does their loss affect gene expression? Aim 2: What is the role of the residual SWI/SNF complex in cancers driven by mutation of SWI/SNF tumor suppressor subunits? Aim 3: What is the relationship between Polycomb complexes and cancers that are driven by SWI/SNF mutations? Significance: Given the increasingly wide spectrum of cancers being found to contain mutations in SWI/SNF subunits, the complex now emerges as having major relevance for human disease. Testing our hypotheses via the proposed specific aims has the potential to elucidate the function of the normal SWI/SNF complex, establish the mechanisms by which mutation of SWI/SNF tumor suppressor subunits drive cancer formation, and identify therapeutic targets for the wide variety of SWI/SNF mutant cancers.

描述（由申请人提供）：新出现的数据表明SWI/SNF染色质重塑复合物是一种主要的肿瘤抑制因子。在过去的两年里，许多癌症基因组测序研究表明，在各种人类癌症中，包括卵巢癌、乳腺癌、肾癌、肺癌、胰腺癌、子宫癌、膀胱癌、胃癌、结肠癌、肝癌和皮肤癌，复合物中至少有六个亚基以高频率特异性失活。SWI/SNF复合物包括核心和谱系特异性亚基，并利用ATP的能量来调节染色质结构。我的实验室已经通过产生基因敲除小鼠模型证明了其中一个亚基的有效和真正的肿瘤抑制作用。提供一些深入的机制，我们最近建立了SWI/SNF和Polycomb复合物之间的表观遗传拮抗作用的存在。然而，SWI/SNF复合物对体内染色质结构的贡献以及每个亚基与不同癌症谱相关的原因仍然知之甚少。鉴于每个亚基中发现的独特的染色质靶向和修饰结构域，我们假设肿瘤发生是由于残余SWI/SNF复合物的差异错误定位和染色质重塑活性的损害。我们进一步假设，SWI/SNF亚基突变导致谱系特异性基因表达程序的破坏，这是由于与Polycomb PRC 2复合物的表观遗传拮抗作用不平衡而引起的。通过以下具体目标，我们的目标是确定SWI/SNF复合物的亚基如何对染色质结构做出贡献，以建立肿瘤抑制子亚基的突变驱动癌症形成的机制，以确定肿瘤抑制子亚基和PRC 2复合物之间的表观遗传拮抗作用的程度，并鉴定SWI/SNF突变癌症的新的有效治疗靶点：单个SWI/SNF肿瘤抑制亚基的丢失如何影响DNA结合、染色质重塑活性和SWI/SNF复合物的完整性，以及它们的丢失如何影响基因表达？目的2：残余SWI/SNF复合物在由SWI/SNF肿瘤抑制亚基突变驱动的癌症中的作用是什么？目的3：多梳复合物与SWI/SNF突变驱动的癌症之间的关系是什么？重要性：鉴于越来越广泛的癌症被发现含有SWI/SNF亚基突变，该复合物现在出现与人类疾病的主要相关性。通过提出的特定目标来验证我们的假设有可能阐明正常SWI/SNF复合物的功能，建立SWI/SNF肿瘤抑制亚基突变驱动癌症形成的机制，并确定各种SWI/SNF突变癌症的治疗靶点。