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

项目概要/摘要 SCCOHT是一种罕见且通常致命的卵巢癌，平均诊断年龄约为24岁 老了SCCOHT的分子发病机制与SMARCA 4基因突变密切相关， 其编码SWI/SNF染色质重塑复合物的BRG 1亚基。大量研究 显示BRG 1的缺失以几种方式影响正常的SWI/SNF功能， 共同驱动SCCOHT表型。SCCOHT癌症属于所有癌症的约20%的组 具有SWI/SNF亚基突变的功能丧失。在这些癌症中， 这可以解释特定SWI/SNF亚基丢失后癌症状态的维持。一 一个共同的发现是，在许多SWI/SNF改变的癌症中，“残留的”SWI/SNF复合物被保留， 功能以促进促肿瘤基因表达程序。第二个更新的发现是， 新出现的是，肿瘤发生的一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，如MYC。最近，致癌MYC靶基因的激活 在SCCOHT中报告了表达，这一现象可能是由于MYC和 SWI/SNF亚基。这个项目是建立在这样一个假设上的，即关键的SWI/SNF亚基的丢失可以1）允许 残余SWI/SNF复合物改变基因表达模式，从而整体促进癌症过程， 2)激活MYC的功能，并可能通过MYC-SWI/SNF相互作用的变化来实现。支持 因为这一假设来自公开的数据，显示在多种SWI/SNF改变的癌细胞系中， 包括SCCOHT，核心残余SWI/SNF亚基在必需MYC靶基因处结合于染色质。 此外，在某些SWI/SNF改变的癌细胞中阻断残留的SWI/SNF复合物功能降低了肿瘤细胞的存活率。 MYC结合基因的表达，表明残留的SWI/SNF复合物可以促进MYC靶向 基因表达。这些数据共同提供了研究剩余SWI/SNF作用的基本原理 亚基和MYC支持SCCOHT中的致癌基因表达程序，并指出 有可能在各种SWI/SNF改变的癌症中存在广泛的，重要的机制。 具体目标1将使用基因组和遗传学方法来评估残留的SWI/SNF亚基是什么 在SCCOHT细胞中的作用以及它们如何影响促肿瘤基因表达。具体目标2将定义 MYC在SCCOHT细胞中的作用，并揭示了残余SWI/SNF亚基和BRG 1 重新引入对MYC活动的影响。在这些研究完成后，我们将知道基因网络 在SCCOHT细胞中由MYC和残余SWI/SNF亚基调节，并直接挑战了 每个驱动SCCOHT功能的多个方面。

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.