The function of Snf5 (SMARCB1), an epigenetic tumor suppressor

表观遗传肿瘤抑制因子 Snf5 (SMARCB1) 的功能

基本信息

批准号：
10308725
负责人：
CHARLES ROBERTS
金额：
$ 41.5万
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：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10308725
关键词：
ATP Hydrolysis ATP phosphohydrolase Automobile Driving Biological Bromodomain CRISPR screen Cancer Etiology Cancer cell line Cell Fate Control Cell Proliferation Cell division Cells Childhood Chromatin Chromatin Remodeling Factor Chromatin Structure Clinical Trials Complex Cues DNA Data Dependence Development Drug resistance EZH2 gene Enhancers Epigenetic Process Excision Family Foundations Funding Genes Genetic Transcription Genetically Engineered Mouse Genomics Goals Hereditary Malignant Neoplasm Heritability Histone Acetylation Histone-Lysine N-Methyltransferase Histones Human In Vitro Interphase Investigation Link Location Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mediating Memory Mitosis Mitotic Modeling Monitor Mus Mutate Mutation Normal Cell Nucleosomes Oncogenic Pathway interactions Phenotype Polycomb Proteins Regulation Regulator Genes Reporting Repression Repressor Proteins Resistance Rhabdoid Tumor Role SMARCA4 gene SMARCB1 gene SWI/SNF Family Complex Syndrome Testing Therapeutic Transcriptional Activation Transcriptional Regulation Tumor Cell Line Tumor Suppressor Proteins Work antagonist base cancer cell cancer predisposition design early childhood epigenetic memory genome-wide head-to-head comparison histone modification in vivo Model inhibitor innovation insight mutant novel novel strategies promoter resistance mechanism response sarcoma therapy resistant tumor tumorigenesis virtual

项目摘要

Project Summary/Abstract: SMARCB1 (SNF5/INI1/BAF47) is a conserved subunit of SWI/SNF chromatin remodeling complexes, which utilize the energy of ATP hydrolysis to mobilize nucleosomes. A role for SWI/SNF complexes in cancer was first suggested when SMARCB1 was identified as inactivated in virtually all cases of malignant rhabdoid tumor (RT), a highly aggressive pediatric cancer. It has recently been discovered that nearly 25% of all human malignancies carry mutations in SWI/SNF subunits. We established SMARCB1 to be a bona fide and potent tumor suppressor and later demonstrated broad epigenetic antagonism between SWI/SNF and Polycomb repressor complexes during oncogenic transformation. In subsequent work, including substantial progress in the current funding period, we uncovered novel biological mechanisms and therapeutic vulnerabilities that form the foundation for the aims described in this proposal. For example, we found that SMARCB1 is essential for enhancer regulation, thus identifying a new mechanism underlying the tumor-suppressive activity of SMARCB1. We and others also discovered the existence of a SWI/SNF complex that lacks SMARCB1, previously considered a core subunit. Instead, this non-canonical complex contains the bromodomain protein BRD9, which we also identified as a specific vulnerability in SMARCB1-deficient pediatric RTs. While our findings demonstrate critical interactions of SWI/SNF and Polycomb complexes in transcriptional regulation and cell fate control, the roles and contributions of SWI/SNF sub-families are unknown. Our first aim is therefore to determine how SMARCB1-containing SWI/SNF complexes differ from mutually-exclusive BRD9- containing SWI/SNF complexes in the antagonism of Polycomb interactions and transcriptional regulation. Recent data from our group have shown that SWI/SNF complexes control histone acetylation and enhancer function; however, the mechanism by which this leads to a mitotically heritable cancer phenotype is unknown. Polycomb complexes remain bound to DNA during mitosis, but histone acetylation is erased and the SWI/SNF ATPase, SMARCA4/BRG1 is phosphorylated and degraded. Thus, for our second aim, we propose to determine how SWI/SNF complexes contribute to epigenetic memory during mitosis, including interrogating a potentially paradigm-shifting model that is supported by preliminary data described in this proposal. Finally, we identified the Polycomb subunit EZH2 as a vulnerability in RTs, inspiring the development of several clinical trials and leading to recent FDA approval of EZH2 inhibitors for SMARCB1-deficient sarcomas. While impactful, resistance to these inhibitors has emerged. To establish mechanisms driving drug resistance, we have performed a near genome-wide CRISPR screen in EZH2 inhibitor-treated RTs, and for our third aim plan to investigate the mechanism of resistance conferred by mutations in a gene not previously associated with SWI/SNF functions. Taken together, these questions have potential for broad and substantive impact in understanding the roles of these critical chromatin remodeling complexes in normal cells and in transformation.

项目摘要/摘要： SMARCB1 (SNF5/INI1/BAF47) 是 SWI/SNF 染色质重塑复合物的保守亚基，利用 ATP 水解的能量来动员核小体。 SWI/SNF 复合物在癌症中的作用是当 SMARCB1 在几乎所有恶性横纹肌瘤病例中被鉴定为失活时首次提出建议 (RT)，一种高度侵袭性的儿童癌症。最近发现，近25%的人类恶性肿瘤携带 SWI/SNF 亚基突变。我们建立 SMARCB1 是为了成为一个真正有效的肿瘤抑制因子，后来证明 SWI/SNF 和 Polycomb 之间具有广泛的表观遗传拮抗作用致癌转化过程中的阻遏复合物。在后续工作中，包括在在当前的资助期间，我们发现了新的生物机制和治疗漏洞，这些机制形成了本提案中描述的目标的基础。例如，我们发现 SMARCB1 对于增强子调节，从而确定了肿瘤抑制活性的新机制 SMARCB1。我们和其他人还发现了缺乏 SMARCB1 的 SWI/SNF 复合体的存在，以前被认为是核心亚基。相反，这种非规范复合物含有溴结构域蛋白 BRD9，我们也将其确定为 SMARCB1 缺陷儿科 RT 中的一个特定漏洞。虽然我们的研究结果表明 SWI/SNF 和 Polycomb 复合物在转录调控中的关键相互作用和细胞命运控制，SWI/SNF 亚家族的作用和贡献尚不清楚。我们的首要目标是因此，要确定包含 SMARCB1 的 SWI/SNF 复合物与互斥的 BRD9 有何不同- 含有 SWI/SNF 复合物，可拮抗 Polycomb 相互作用和转录调控。我们小组的最新数据表明 SWI/SNF 复合物控制组蛋白乙酰化和增强子功能;然而，这导致有丝分裂遗传性癌症表型的机制尚不清楚。在有丝分裂过程中，多梳复合物仍与 DNA 结合，但组蛋白乙酰化被消除，SWI/SNF ATPase、SMARCA4/BRG1 被磷酸化并降解。因此，对于我们的第二个目标，我们建议确定 SWI/SNF 复合物如何在有丝分裂期间促进表观遗传记忆，包括询问本提案中描述的初步数据支持潜在的范式转变模型。最后，我们将 Polycomb 亚基 EZH2 确定为 RT 中的一个漏洞，激发了多种临床研究的开发试验并导致 FDA 最近批准 EZH2 抑制剂治疗 SMARCB1 缺陷肉瘤。尽管影响深远，对这些抑制剂的耐药性已经出现。为了建立驱动耐药性的机制，我们在 EZH2 抑制剂处理的 RT 中进行了近基因组范围的 CRISPR 筛选，这是我们的第三个目标计划研究先前与病毒无关的基因突变所产生的耐药机制 SWI/SNF 功能。总而言之，这些问题有可能对以下方面产生广泛和实质性的影响：了解这些关键染色质重塑复合物在正常细胞和转化中的作用。