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

• 批准号: 8689980
• 负责人: CHARLES ROBERTS
• 金额: $ 34.85万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/8689980
• 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

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）：新兴数据将SWI/SNF染色质重塑复合物作为主要肿瘤抑制剂。在过去的[两年]中，众多癌症基因组测序研究表明，该复合物的至少六个亚基在各种人类癌症（包括卵巢，乳腺癌，肾脏，肺，胰腺，子宫，子宫，淡水，淡水，胃，胃，结肠，肝脏，肝脏和皮肤）中，在高频中特异性灭活。 SWI/SNF络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。我的实验室证明了通过产生敲除小鼠模型的一个亚基的有效和真正的肿瘤抑制作用。为了对机制提供一些洞察力，我们最近确定了SWI/SNF和PolyComb复合物之间的表观遗传拮抗作用。但是，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光谱相关的原因。鉴于每个亚基中发现的独特的染色质靶向和修饰域，我们假设发生了肿瘤发生，这是由于残留SWI/SNF复合物的差异和染色质重塑活性的损害而发生的。我们进一步假设SWI/SNF亚基突变会导致谱系特异性基因表达程序的破坏是由Polycomb Prc2复合物的表观遗传拮抗作用不平衡的。通过以下特定目的，我们的目标是确定SWI/SNF复合物的亚基如何促进染色质结构，以建立肿瘤抑制亚基突变的机制，以促进癌症的形成，以确定肿瘤抑制剂和有效的snf snf的肿瘤抑制剂和有效的snf snf的肿瘤抑制剂之间的表观遗传对抗的程度：单个SWI/SNF肿瘤抑制亚基影响DNA结合，染色质重塑活性以及SWI/SNF复合物的完整性，它们的损失如何影响基因表达？ AIM 2：由SWI/SNF抑制亚基突变驱动的残留SWI/SNF复合物在癌症中的作用是什么？ AIM 3：由SWI/SNF突变驱动的Polycomb复合物与癌症之间的关系是什么？意义：鉴于发现在SWI/SNF亚基中含有突变的癌症越来越广泛，因此该综合体现在与人类疾病具有重要意义。通过提出的特定目的测试我们的假设有可能阐明正常SWI/SNF复合物的功能，建立SWI/SNF肿瘤抑制亚基突变的机制，并确定各种SWI/SNF突变突变剂的治疗靶标。