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： 癌症基因组的系统测序揭示了编码基因突变的较高流行率 染色质调节蛋白。在这些畸变中，编码SWI/SNF亚基的基因突变（BAF） 染色质复制络合物是最常见的，统称为所有癌症的20％以上。 尽管已经研究了在癌症中如此高频率突变的大多数基因已有数十年的研究 最近对SWI/SNF突变的重要作用的认识更为最近。 SWI/SNF和 当发现编码SMARCB1亚基的基因几乎被双向灭活时，癌症就发生了。 所有高度侵略性和致命癌症早期癌症的病例均称为恶性胸腺肿瘤（RT）。 值得注意的是，这些RT癌症在基因组上是稳定和二倍体的，使它们成为一个非常有用的模型 研究SWI/SNF破坏的影响。我们的长期目标是阐明SWI/SNF的功能 复合物，确定它们的损失如何导致肿瘤发生，并将这种理解转化为新颖 高效的疗法。我们的小组确立了Smarcb1是真正的肿瘤抑制剂，并且 后来进行了高影响的发现，有助于定义SWI/SNF突变导致的机制 细胞增殖失调。迄今 转录是细胞命运规范的基础，而该控制的破坏是癌症的基础 形成。我们假设损失SMARCB1在推动癌症生长的同时也创造了独特的 漏洞。为了识别此类漏洞，我们进行了一个严格的屏幕，涉及21个RT单元线 与其他800个癌细胞系相比。在此屏幕上，我们确定并随后验证了两项小说 对于RT细胞存活而言，基因是特异性和有效的基因。使用多种方法和工具，我们 已经验证了这两个基因在RT细胞中特别重要的基因。我们随后的初步数据表明，这两者都 基因在染色质调节中具有意外的新作用：既调节活性染色质，又有特定的 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复合物合作，并且阐明其功能将会 提供对染色质介导的转录调节的新见解，该机制的突变 SWI/SNF亚基驱动癌症，以及由SWI/SNF突变产生的漏洞。另外，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 在这些基因和SWI/SNF之间，并确定RT中特定漏洞的基础机制。 综上所述，这些努力通过扩大对 正常细胞和转化中的染色质调节剂，并通过识别高度特异性的新治疗剂 这些致命儿童期癌症的靶标。