SWI/SNF Chromatin Remodeling Loss and Human Cancer

SWI/SNF 染色质重塑损失与人类癌症

• 批准号: 7267012
• 负责人: Bernard E. Weissman
• 金额: $ 27.49万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267012
• 关键词: Address; Adenocarcinoma; Biochemical; Biological; Biological Response Modifiers; CD44 gene; CDKN1A gene; Cadherins; Cell Cycle Arrest; Cell Cycle Regulation; Cell Line; Cells; Chimeric Proteins; Chromatin Remodeling Factor; Chromatin Structure; Complex; Cultured Cells; DNA; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; Detection; Development; Dissection; E-Cadherin; E-Cadherin Staining Method; Embryo; Energy Supply; Epithelial Cells; Etiology; Fibroblasts; Frequencies; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Genomic Imprinting; Genomic Instability; Histone Deacetylase; Homologous Gene; Human; Human Development; Incidence; Lung Neoplasms; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mating Types; Mediating; Metastasis Suppressor Genes; Methylation; Modeling; Mus; Mutation; Neoplasms; Neoplastic Cell Transformation; Non-Small-Cell Lung Carcinoma; Nucleosomes; Oncogenes; Pathway interactions; Phenotype; Play; Positioning Attribute; Predisposition; Primary Neoplasm; Process; Property; Proteins; Reporting; Rhabdoid Tumor; Role; SMARCA1 gene; SMARCA4 gene; SMARCB1 gene; Sampling; Specific qualifier value; Sucrose; Testing; Tracheobronchial; Transcription Coactivator; Tumor Cell Line; Tumor Suppressor Genes; Yeasts; base; brahma; cell growth regulation; chromatin remodeling; gene function; human disease; implantation; insight; loss of function; lung Carcinoma; neoplastic cell; oncoprotein p21; promoter; protein function; tumor; tumor progression

DESCRIPTION (provided by applicant): The identification of tumor suppressor genes has led to new insights into the mechanisms of human cancer development. The normal functions of these genes often lie in the control of gene expression, especially in the realm of cell cycle control and cellular differentiation. Several recent studies have implicated aberrant activity of chromatin remodeling complexes in the development of human cancer. Mutations in the INI1/SNF5 gene, a component of the SWI/SNF chromatin remodeling complex, occur in the majority of malignant rhabdoid tumors. The SWI/SNF complex acts as a global transcriptional activator that alters nucleosome positioning on DNA via an energy-dependent mechanism. Others and we have also demonstrated the loss and/or mutations of both human SWI2 homologs, BRG1 and BRM, in human tumor cell lines and primary tumors. Loss of expression of both proteins abrogates Rb-mediated cell cycle arrest. However either protein appears to regulate the expression of key cancer progression genes including Ecadherin and CD44. Furthermore, while BRG1v/- mice develop adenocarcinomas, BRM-/- mice do not show an increased tumor incidence. Therefore, the mechanism by which loss of expression of either or both proteins contributes to the etiology of human cancers remains unresolved. We have observed an association between BRG1-induced gene expression and loss of promoter methylation in human tumor cells, especially Non-Small Cell Lung Carcinomas (NSCLC). Based on these studies, we hypothesize that loss of SWI/SNF complex activity through inactivation of BRG1 and/or BRM fuels genomic instability during human tumor progression by facilitating gene silencing through DNA methylation. To test this hypothesis, we require a better understanding how loss of expression of BRG1 and BRM proteins alters the biological properties of tumor cells and the chromatin structure of cancer related genes. In this application, we will identify overlapping and independent biological and biochemical functions of these proteins in the first specific aim. In the second specific aim, we will determine how the loss of these proteins contributes to lung tumor development using a human tracheobronchial cell culture model. In the last specific aim, we will characterize the effects of BRG1 and BRM loss on the chromatin structure and DNA methylation status of important target genes. The dissection of the role of these genes in human cancer development will broaden our understanding of their normal biological and biochemical functions, provide new insights into the control of DNA methylation and impact upon treatment and detection of this clinically important tumor.

描述（由申请人提供）：鉴定肿瘤抑制基因已导致对人类癌症发育机制的新见解。这些基因的正常功能通常在于基因表达的控制，尤其是在细胞周期控制和细胞分化领域。最近的一些研究表明，染色质重塑复合物在人类癌症的发展中的异常活性。 INI1/SNF5基因中的突变是SWI/SNF染色质重塑复合物的一个成分，发生在大多数恶性胸腺肿瘤中。 SWI/SNF复合物充当一种全局转录激活剂，通过能量依赖性机制来改变在DNA上的核小体定位。其他人也证明了人类肿瘤细胞系和原发性肿瘤中人类SWI2同源物，BRG1和BRM的损失和/或突变。两种蛋白质的表达丧失都消除了RB介导的细胞周期停滞。但是，任何一种蛋白似乎都调节包括eCadherin和CD44在内的关键癌症进展基因的表达。此外，虽然BRG1V/ - 小鼠发展腺癌，但BRM - / - 小鼠并未显示出肿瘤发病率增加。因此，任何一种或两种蛋白质的表达丧失导致人类癌症的病因的机制尚未解决。我们已经观察到BRG1诱导的基因表达与人类肿瘤细胞中启动子甲基化丧失之间的关联，尤其是非小细胞肺癌（NSCLC）。基于这些研究，我们假设通过通过促进通过DNA甲基化促进基因沉默的人类肿瘤进展过程中BRG1和/或BRM燃料基因组不稳定性的失活而丧失了SWI/SNF复合活性。为了检验这一假设，我们需要更好地理解BRG1和BRM蛋白表达丧失如何改变肿瘤细胞的生物学特性和癌症相关基因的染色质结构。在此应用中，我们将在第一个特定目标中确定这些蛋白质的重叠和独立的生物学和生化功能。在第二个特定目的中，我们将确定这些蛋白质的丧失如何使用人类气管支气管内细胞培养模型有助于肺部肿瘤的发展。在最后一个特定目标中，我们将表征BRG1和BRM损失对重要靶基因的染色质结构和DNA甲基化状态的影响。这些基因在人类癌症发育中的作用的解剖将扩大我们对它们正常的生物学和生化功能的理解，为控制DNA甲基化的控制提供了新的见解，并对治疗和检测该临床重要肿瘤的治疗和检测产生了影响。