Cancer-based discovery of novel mechanisms of chromatin control

基于癌症的染色质控制新机制的发现

• 批准号: 10660680
• 负责人: CHARLES ROBERTS
• 金额: $ 41.63万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-06 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660680
• 关键词: Acetylation; Adult; Automobile Driving; Binding; Biology; Bypass; CRISPR/Cas technology; Cancer cell line; Cell Death; Cell Proliferation; Cell Survival; Cells; Childhood; Childhood Precursor T Lymphoblastic Leukemia; Chromatin; Chromatin Remodeling Factor; Clinical Trials; Coffin-Siris Syndrome; Complex; Cullin Proteins; DNA Polymerase II; Data; Defect; Dependence; Diploidy; Disease; Drosophila snf protein; EZH2 gene; Enhancers; Frequencies; Gene Mutation; Genes; Genetic; Genetic Transcription; Genome; Genome Stability; Goals; Growth; Hereditary Malignant Neoplasm; High Prevalence; Histone H3; Histones; Lead; Link; Lysine; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modeling; Mutate; Mutation; Nature; Neurodevelopmental Disorder; Normal Cell; Pediatric Neoplasm; Proteins; RNA; Recurrence; Regulation; Residual state; Rhabdoid Tumor; Role; SMARCB1 gene; SWI/SNF Family Complex; Specific qualifier value; Syndrome; Testing; Therapeutic; Toxic effect; Transcriptional Regulation; Translating; Tumor Cell Line; Tumor Suppressor Proteins; Work; Xenograft procedure; Zinc Fingers; antagonist; cancer cell; cancer genome; cancer genomics; cancer predisposition; design; early childhood; effective therapy; genetic regulatory protein; genome wide screen; in vivo evaluation; inhibitor; insight; mutant; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; promoter; receptor; recruit; sarcoma; therapeutic target; tool; translational therapeutics; tumor growth; tumorigenesis; ubiquitin-protein ligase

Project Summary/Abstract: The systematic sequencing of cancer genomes has revealed a high prevalence of mutations in genes encoding chromatin regulatory proteins. Of these aberrations, mutations in genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are the most frequent, collectively occurring in over 20% of all cancers. Whereas most genes that are mutated at such high frequencies in cancer have been studied for many decades, recognition of a prominent role for SWI/SNF mutations is much more recent. The first link between SWI/SNF and cancer came when the gene encoding the SMARCB1 subunit was found to be biallelically inactivated in nearly all cases of the highly aggressive and lethal cancer of early childhood termed malignant rhabdoid tumor (RT). Notably, these RT cancers are genomically stable and diploid, rendering them a highly useful model in which to study the effects of SWI/SNF disruption. Our long-term goals are to elucidate the function of SWI/SNF complexes, to determine how their loss leads to oncogenesis, and to translate this understanding into novel highly effective therapies. Our group established SMARCB1 to be a bona fide and potent tumor suppressor and later made high-impact discoveries that help define mechanisms by which SWI/SNF mutations lead to dysregulated cell proliferation. Our findings to date suggest a model whereby SWI/SNF-facilitated control of transcription underlies cellular fate specification, with disruption of this control being the basis for cancer formation. We hypothesized that loss of SMARCB1, while driving cancer growth, also creates unique vulnerabilities. To identify such vulnerabilities, we undertook a rigorous screen involving 21 RT cell lines compared to 800 other cancer cell lines. From this screen, we identified and subsequently validated two novel genes as being required specifically and potently for RT cell survival. Using multiple approaches and tools, we have validated both genes as specifically essential in RT cells. Our subsequent preliminary data reveal that both genes have unanticipated novel roles in chromatin regulation: both regulate active chromatin and specifically facilitate acetylation of lysine residues on histone H3 that facilitate transcription of target genes. We now hypothesize that these genes cooperate with SWI/SNF complexes, and that elucidation of their function will provide novel insights into chromatin-mediated regulation of transcription, mechanisms by which mutation of SWI/SNF subunits drive cancer, and vulnerabilities created by SWI/SNF mutations. Additionally, both genes bring the opportunity for therapeutic targeting. In the proposed work, we will define the mechanistic relationship between these genes and SWI/SNF and determine the mechanism underlying the specific vulnerabilities in RT. Taken together, these efforts have potential for substantial impact by broadening understanding of the roles of chromatin regulators in normal cells and in transformation and by identifying highly specific new therapeutic targets for these lethal childhood cancers.

项目摘要/摘要： 对癌症基因组的系统测序揭示了编码基因突变的高发 染色质调节蛋白。在这些异常中，编码SWI/SNF(BAF)亚单位的基因突变 染色质重塑复合体是最常见的，在所有癌症中共同出现的比例超过20%。 虽然在癌症中以如此高的频率突变的大多数基因已经被研究了几十年， 对SWI/SNF突变的显著作用的认识要晚得多。SWI/SNF之间的第一个链接 当编码SMARCB1亚单位的基因被发现在几乎 所有儿童早期高度侵袭性和致命性癌症均称为恶性横纹肌样瘤(RT)。 值得注意的是，这些RT癌症在基因组上是稳定的和二倍体的，使它们成为一种非常有用的模型，在其中 研究SWI/SNF中断的影响。我们的长期目标是阐明SWI/SNF的功能 确定它们的丢失如何导致肿瘤发生，并将这一理解转化为小说 非常有效的疗法。我们小组证实SMARCB1是一种真正有效的肿瘤抑制因子， 后来做出了影响巨大的发现，帮助定义了SWI/SNF突变导致 失调的细胞增殖。到目前为止，我们的研究结果表明，SWI/SNF促进了对 转录是细胞命运指定的基础，而这种控制的破坏是癌症的基础 队形。我们假设，SMARCB1的缺失，在推动癌症生长的同时，也会产生独特的 漏洞。为了识别这种脆弱性，我们进行了一项涉及21个RT细胞系的严格筛选 相比之下，其他800种癌细胞株。从这个屏幕上，我们识别并随后验证了两部小说 RT细胞生存所需的特异和有效的基因。使用多种方法和工具，我们 已经证实这两个基因在RT细胞中是特定必需的。我们随后的初步数据显示， 基因在染色质调节中具有意想不到的新作用：既调节活性染色质，又特异地 促进组蛋白H3上赖氨酸残基的乙酰化，从而促进靶基因的转录。我们现在 假设这些基因与SWI/SNF复合体协同作用，且对它们功能的阐明将 为染色质介导的转录调控提供了新的见解， SWI/SNF亚基驱动癌症，SWI/SNF突变造成的脆弱性。此外，这两个基因 带来治疗靶向的机会。在拟议的工作中，我们将定义机械关系 这些基因和SWI/SNF之间的关系，并确定RT中特定漏洞的潜在机制。 综上所述，这些努力可能会产生重大影响，因为它扩大了对 染色质调节剂在正常细胞和转化中以及通过识别高度特异的新疗法 这些致命的儿童癌症的目标。