SOX2-MYC Axis: Transcriptional Repression of the MYC Oncogene by SOX2

SOX2-MYC 轴：SOX2 对 MYC 癌基因的转录抑制

• 批准号: 10511895
• 负责人: A. ANGIE RIZZINO
• 金额: $ 7.68万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511895
• 关键词: 3-Dimensional; Address; Binding; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Cells; Chromatin Loop; Chromatin Structure; Clinical; Complex; Data Analyses; Development; Distal; Down-Regulation; Doxycycline; Engineering; Enhancers; Failure; Gene set enrichment analysis; Genes; Genetic Transcription; Goals; Growth; Human; LNCaP; Link; MYC gene; Malignant Neoplasms; Molecular; Organ; Play; Population; Positioning Attribute; Proliferating; Prostate; Proteins; RNA; Recurrence; Residual state; Resistance; Response Elements; Role; Structure; Testing; Transactivation; Tumor Cell Line; WNT Signaling Pathway; Work; anticancer research; base; beta catenin; c-myc Genes; cancer recurrence; cancer therapy; cell growth; cell type; chromatin immunoprecipitation; chromosome conformation capture; conventional therapy; fetal stem cell; gene repression; histone modification; in vivo; medulloblastoma; neoplastic cell; new therapeutic target; novel; promoter; response; small molecule inhibitor; stem cells; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor growth

ABSTRACT A wide array of strategies and small molecule inhibitors have been identified that target actively proliferating tumor cells. However, quiescent tumor cells are largely resistant to conventional therapies used to eliminate proliferating tumor cells. Hence, quiescent tumor cells pose a major clinical challenge and a significant unmet need in the treatment of cancer, because quiescent cells represent a residual population of tumor cells that can drive tumor recurrence. To address this unmet need, we have been studying the transcription factor SOX2, whose elevated expression has been shown to restrict the proliferation of many different tumor cell types as well as the proliferation of normal fetal stem cells. Our work has established that elevating SOX2 from an inducible promoter in multiple tumor cell types invariably leads to growth inhibition. Moreover, we determined that elevating SOX2 in vivo leads to a reversible state of tumor growth arrest, where tumor growth resumes when SOX2 returns to endogenous levels. To determine how SOX2 restricts tumor cell growth, we examined how elevating SOX2 alters the transcriptome in different tumor cell types. These studies demonstrated that elevation of SOX2 downregulates MYC expression and the expression of MYC target genes. To extend these findings, we performed a MYC rescue study and determined that failure to downregulate MYC when SOX2 is elevated is deleterious to the cells. Thus, this newly discovered SOX2:MYC axis appears to play a critical role in growth inhibition when SOX2 is elevated. Equally important, we determined that elevating SOX2 downregulates MYC at the transcriptional level. The studies proposed here seek to determine how elevating SOX2 decreases MYC transcription. In proliferating cells, MYC transcription is dependent on multiple distal enhancers that activate the MYC promoter via chromatin loops whose formation is dependent on the binding of β-catenin to Wnt Response Elements (WREs) present in each MYC enhancer. Importantly, SOX2 has been shown to interfere with Wnt signaling by its interaction with β-catenin via the R1 transactivation domain of SOX2, which we recently determined is required to inhibit tumor cell growth and downregulate MYC. Based on these findings, we hypothesize that elevating SOX2 downregulates MYC expression by interfering with the function of transcription factors that promote the formation of critical long-range enhancer-promoter interactions required to drive MYC transcription. This hypothesis will be tested by two Specific Aims. Aim 1 will determine how elevating SOX2 alters the 3-D chromatin structure of the MYC locus. Aim 2 will determine whether elevating SOX2 alters the binding of transcription factors to MYC enhancers, changes histone modifications found at active MYC enhancers, and/or blocks the formation of the transcription preinitiation complex at the MYC promoter. Understanding how elevating SOX2 downregulates MYC would be highly significant, because little is known about the links between these two master regulators. Ultimately, we believe our studies will lead to the discovery of novel druggable targets to eradicate quiescent tumor cells implicated in cancer recurrence.

抽象的 已经确定了各种各样的策略和小分子抑制剂，这些策略会积极增殖的靶标 肿瘤细胞。但是，静止的肿瘤细胞在很大程度上对消除的常规疗法具有抗性 增殖的肿瘤细胞。因此，静止的肿瘤细胞构成了重大的临床挑战，并且显着未经许可 在癌症治疗中的需要，因为静态细胞代表了可以 驱动肿瘤复发。为了满足这种未满足的需求，我们一直在研究转录因子SOX2， 其表达的升高也已被证明限制了许多不同肿瘤细胞类型的增殖 作为正常胎儿干细胞的增殖。我们的工作已经确定使Sox2从可诱导的 多种肿瘤细胞类型中的启动子总是会导致抑制作用。此外，我们确定了提升 Sox2体内导致可逆的肿瘤生长停滞状态，当Sox2返回时肿瘤生长恢复 到内源性水平。为了确定SOX2如何限制肿瘤细胞生长，我们检查了如何升高SOX2 改变不同肿瘤细胞类型中的转录组。这些研究表明Sox2的升高 下调MYC的表达和MYC靶基因的表达。为了扩展这些发现，我们 进行了MYC救援研究，并确定当Sox2升高时未能下调MYC 对细胞有害。那是这个新发现的SOX2：MYC轴似乎在成长中起着关键作用 SOX2升高时的抑制作用。同样重要的是，我们确定提升Sox2下调MYC 在转录级别。这里提出的研究试图确定Sox2如何降低MYC 转录。在增殖的细胞中，MYC转录取决于激活该激活的多个盘式增强子 MYC通过染色质环的启动子，其形成取决于β-catenin与Wnt反应的结合 每个MYC增强器中存在的元素（WRE）。重要的是，Sox2已显示出干扰Wnt 通过与β-catenin的相互作用通过SOX2的R1反式激活结构域的信号传导，我们最近 确定需要抑制肿瘤细胞生长并下调MYC。基于这些发现，我们 假设升高Sox2通过干扰转录功能下降了MYC的表达 促进驱动MYC所需的关键远程增强子促销相互作用的重要因素 转录。该假设将通过两个具体目标来检验。 AIM 1将决定抬高Sox2如何改变 MYC基因座的3-D染色质结构。 AIM 2将确定抬高Sox2是否改变了结合 MYC增强剂的转录因子，在活跃MYC增强剂中发现的组蛋白修饰变化，/或 阻止MYC启动子上转录预原始复合物的形成。了解如何提升 Sox2下调MYC将非常重要，因为这些之间的联系知之甚少 两个主调节器。最终，我们认为我们的研究将导致发现新颖的可吸毒目标 根除在癌症复发中实施的静态肿瘤细胞。