Exposing the role of MYC in small cell carcinoma of the ovary hypercalcemic type

揭示 MYC 在卵巢高钙血症型小细胞癌中的作用

• 批准号: 10728702
• 负责人: April M. Weissmiller
• 金额: $ 6.57万
• 依托单位: MIDDLE TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728702
• 关键词: ATP phosphohydrolase; Acute; Affect; Age; Automobile Driving; Binding; Biologic Characteristic; Biological Assay; Cancer cell line; Cell Line; Cell physiology; Chromatin; Chromatin Remodeling Factor; Data; Diagnosis; Essential Genes; Exposure to; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomic approach; Goals; Hypercalcemia; Image; Impairment; Left; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Modeling; Molecular; Mutation; Oncogenes; Oncogenic; Oncoproteins; Operative Surgical Procedures; Ovarian; Ovarian Carcinoma; Pathogenesis; Patients; Phenotype; Play; Process; Proteins; Publishing; Recurrence; Recurrent disease; Regulation; Reporting; Residual Cancers; Residual state; Role; SMARCA4 gene; SMARCB1 gene; SMARCC1 gene; SWI/SNF Family Complex; Shapes; Small Cell Carcinoma; Testing; Tumor Suppression; Tumor Suppressor Proteins; Woman; Work; cancer cell; cancer type; cell type; chemotherapy; falls; gene network; genetic approach; genome-wide; inducible gene expression; loss of function; novel; novel therapeutic intervention; predictive modeling; programs; protein complex; transcription factor; transcriptome; transcriptome sequencing; tumor; tumorigenesis; tumorigenic; young woman

PROJECT SUMMARY/ABSTRACT SCCOHT is rare and often fatal ovarian cancer, with the average age of diagnosis being around 24 years old. The molecular pathogenesis of SCCOHT is overwhelmingly linked to mutations in the SMARCA4 gene, which encodes the BRG1 subunit of the SWI/SNF chromatin remodeling complex. Numerous studies have shown that loss of BRG1 impacts normal SWI/SNF function in several ways, which together most likely conspire to drive the SCCOHT phenotype. SCCOHT cancers fall into a group of about 20% of all cancers that have loss-of-function SWI/SNF subunit mutations. Across these cancers mechanisms are emerging that can explain the maintenance of the cancer state following loss of particular SWI/SNF subunits. One common finding is that in many SWI/SNF-altered cancers “residual” SWI/SNF complexes are retained that function to promote a pro-tumorigenic gene expression program. A second and more new finding that is emerging is that some underlying mechanisms of tumorigenesis may involve interactions between SWI/SNF and oncoprotein transcription factors, such as MYC. Recently, activation of oncogenic MYC target gene expression was reported in SCCOHT, a phenomenon that may be due to interactions between MYC and SWI/SNF subunits. This project is built on the hypothesis that loss of critical SWI/SNF subunits can 1) allow residual SWI/SNF complexes to alter gene expression patterns that overall promote cancer processes and 2) activate the functionality of MYC and may do so through changes in MYC-SWI/SNF interactions. Support for this hypothesis comes from published data showing that in multiple SWI/SNF-altered cancer cell lines, including SCCOHT, core residual SWI/SNF subunits are bound to chromatin at essential MYC target genes. In addition, blocking residual SWI/SNF complex function in certain SWI/SNF-altered cancer cells decreases expression of genes bound by MYC, suggesting that residual SWI/SNF complexes can facilitate MYC-target gene expression. Together these data provide the rationale for examining the role of residual SWI/SNF subunits and MYC in supporting oncogenic gene expression programs in SCCOHT, and point to the possibility there there are broad, significant mechanisms at work across various SWI/SNF-altered cancers. Specific Aim 1 will use genomic and genetic approaches to assess what residual SWI/SNF subunits are doing in SCCOHT cells and how they influence pro-tumorigenic gene expression. Specific Aim 2 will define the action of MYC in SCCOHT cells and expose the impact that both residual SWI/SNF subunits and BRG1 reintroduction has on MYC activities. At the completion of these studies we will know the gene networks regulated by MYC and residual SWI/SNF subunits in SCCOHT cells and directly challenged the significance of each in driving multiple facets of SCCOHT function.

项目摘要/摘要 SCCOHT很少见，通常是致命的卵巢癌，诊断的平均年龄约为24岁 老的。 SCCOHT的分子发病机理与Smarca4基因中的突变完全关联 它编码SWI/SNF染色质重塑复合物的BRG1亚基。有许多研究 表明BRG1的丢失会以多种方式影响正常的SWI/SNF功能，这很可能在一起 合谋推动SCCOHT表型。 SCCOHT癌症属于大约20％的所有癌症 具有功能丧失的SWI/SNF亚基突变。在这些癌症机制中正在出现 这可以解释特定SWI/SNF亚基的损失后癌症状态的维持。一 普遍发现是，在许多改变的SWI/SNF癌症中，保留了“残留” SWI/SNF复合体 促进促肿瘤基因表达程序的功能。第二个和更多的发现是 新兴的是，肿瘤发生的某些潜在机制可能涉及SWI/SNF之间的相互作用 和癌蛋白转录因子，例如MYC。最近，致癌MYC靶基因的激活 在SCCOHT中报道了表达，这可能是由于MYC和MYC之间的相互作用引起的 SWI/SNF亚基。该项目建立在以下假设的基础上，即损失关键SWI/SNF亚基可以1）允许 残留的SWI/SNF复合物改变基因表达模式，总体促进癌症过程和 2）激活MYC的功能，并可以通过更改MYC-SWI/SNF相互作用来进行。支持 对于这一假设，来自公开的数据，表明在多个SWI/SNF改变的癌细胞系中， 包括SCCOUT，核心残留的SWI/SNF亚基在基本MYC靶基因上呈染色质。 此外，在某些SWI/SNF改变的癌细胞中阻止残留的SWI/SNF复合功能下降 MYC约束的基因表达，表明残留的SWI/SNF复合物可以促进Myc-target 基因表达。这些数据共同提供了检查残留SWI/SNF的作用的理由 亚基和MYC支持SCCOHT中的致癌基因表达程序，并指向 在各种SWI/SNF改变的癌症中，有可能起作用的重要机制。 具体目标1将使用基因组和遗传方法评估哪些残留SWI/SNF亚基是 在SCCOHT细胞中进行及其如何影响促肿瘤基因表达。特定目标2将定义 MYC在SCCOHT细胞中的作用，并暴露了残留的SWI/SNF亚基和BRG1的影响 重新引入的MYC活动。完成这些研究时，我们将知道基因网络 由MYC和残留的SWI/SNF亚基在SCCOHT细胞中调节，并直接挑战了重要性 驱动SCCOHT功能多个方面的每个方面。