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: 10673740
• 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/10673740
• 关键词: 3-Dimensional; Acceleration; 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; Recurrent Malignant Neoplasm; Recurrent tumor; Residual state; Resistance; Response Elements; Role; Structure; Testing; Transactivation; Tumor Cell Line; WNT Signaling Pathway; Work; anticancer research; 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 各种各样的策略和小分子抑制剂已成为目标靶靶标积极地延伸 但是，肿瘤细胞。 增殖的肿瘤细胞。 需要治疗癌症，因为静态细胞细胞肿瘤细胞可以 驱动肿瘤复发。 其表达升高是限制了许多不同肿瘤细胞类型的增殖 随着正常胎儿干细胞的延长，我们的工作已经从诱导的 多种肿瘤细胞类型中的启动子不变导致生长抑制作用。 Sox2体内导致可逆的肿瘤生长状态 为了确定Sox2如何限制肿瘤细胞的生长，我们检查了Sox2 在不同的肿瘤细胞类型中改变转录表明SOX2的升高 下调MYC的表达和MYC靶基因的表达。 进行了MYC救援研究，并设计了Soux2升高时未能下调MYC 因此，这个新发现的Sox2：Myc轴似乎在生长中起关键作用 当Sox2升高时，抑制作用同样重要。 在转录水平上。 转录。 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增强器中都存在的元素（WRES）。 通过SOX2的R1反式激活结构域与 - 连环蛋白的信号传导交联，我们最近 根据这些发现，确定抑制肿瘤细胞生长并下调MYC。 假设抬高Sox2通过干扰转录功能，从而下调了MYC Express 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。 MYC基因座的3-D染色质结构。 MYC增强剂的转录因子，耐心MYC增强剂发现的组蛋白修饰和/或或或或或或或或或 阻止在MYC启动子上的转录率通信的形成 Sox2下调了Myc WOOLD非常重要，因为这些之间的联系知之甚少 两个主要监管机构。 根除与癌症复发有关的静态肿瘤细胞。