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

表观遗传肿瘤抑制因子 Snf5 (SMARCB1) 的功能

• 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
• 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

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染色质重塑复合体的保守亚基。 利用ATP水解的能量来动员核小体。SWI/SNF复合体在癌症中的作用 首次提出当SMARCB1在几乎所有恶性横纹肌样瘤病例中被确定为失活时 (RT)，一种高度侵袭性的儿科癌症。最近发现，近25%的人类 恶性肿瘤携带SWI/SNF亚单位的突变。我们确定SMARCB1是一个真诚和强大的 肿瘤抑制因子及后来证实SWI/SNF和Polycomb之间广泛的表观遗传拮抗作用 抑制子复合体在致癌转化中的作用。在随后的工作中，包括在 在当前的资助期内，我们发现了新的生物机制和治疗脆弱性 这是本提案中所述目标的基础。例如，我们发现SMARCB1对于 增强子调控，从而确定了一种新的潜在的肿瘤抑制活性的机制 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单位。相反，这种非规范的复合体含有溴域蛋白。 BRD9，我们还发现它是SMARCB1缺陷的儿科RTS中的一个特定漏洞。而我们的 结果表明SWI/SNF和Polycomb复合体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，为了确定含有SMARCB1的SWI/SNF复合体与互斥的BRD9- 含有SWI/SNF复合体的多梳相互作用的拮抗和转录调控。 我们小组的最新数据表明，SWI/SNF复合体控制组蛋白乙酰化和增强子 功能；然而，这导致有丝分裂可遗传癌症表型的机制尚不清楚。 在有丝分裂期间，多梳复合体仍与DNA结合，但组蛋白乙酰化被擦除，SWI/SNF ATPase、SMARCA4/BRG1被磷酸化和降解。因此，对于我们的第二个目标，我们建议 确定SWI/SNF复合体如何在有丝分裂过程中促进表观遗传记忆，包括询问 潜在的范式转换模型，由本提案中描述的初步数据支持。最后，我们 发现多梳亚单位EZH2是RTS中的一个漏洞，启发了几个临床 试验并导致最近FDA批准EZH2抑制剂治疗SMARCB1缺陷肉瘤。而当 对这些抑制剂产生了有效的抗药性。为了建立驱动抗药性的机制，我们 我们在EZH2抑制剂治疗的RTS中进行了几乎全基因组的CRISPR筛查，并为我们的第三个Aim计划 为了研究一种以前没有关联的基因突变所产生的耐药性的机制 SWI/SNF功能。综上所述，这些问题有可能在以下方面产生广泛和实质性的影响 了解这些关键的染色质重塑复合体在正常细胞和转化中的作用。