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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的已经确定了一系列针对活跃增殖的策略和小分子抑制剂然而，静止的肿瘤细胞对消除肿瘤细胞的传统疗法有很大的抵抗力。因此，静止的肿瘤细胞构成了重大的临床挑战和重大的未满足的问题。癌症治疗中的需要，因为静止细胞代表了肿瘤细胞的残余群体，可以为了解决这一未满足的需求，我们一直在研究转录因子 SOX2，其表达升高已被证明可以限制许多不同肿瘤细胞类型的增殖我们的工作已经确定，SOX2 可以从诱导型细胞中增殖。多种肿瘤细胞类型中的启动子总是会导致生长抑制。 SOX2在体内导致肿瘤生长停滞的可逆状态，当SOX2恢复时肿瘤生长恢复为了确定 SOX2 如何限制肿瘤细胞生长，我们研究了如何升高 SOX2。这些研究表明 SOX2 的升高会改变不同肿瘤细胞类型的转录组。下调 MYC 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 因此，这种新发现的 SOX2:MYC 轴似乎在生长中发挥着关键作用。 SOX2 升高时的抑制同样重要，我们确定升高 SOX2 会下调 MYC。本文提出的研究旨在确定升高 SOX2 如何降低 MYC。在增殖细胞中，MYC 转录依赖于激活 MYC 的多个远端增强子。 MYC 启动子通过染色质环，其形成取决于 β-连环蛋白与 Wnt 反应的结合每个 MYC 增强子中存在的元素 (WRE) 重要的是，SOX2 已被证明会干扰 Wnt。通过 SOX2 的 R1 反式激活结构域与 β-catenin 相互作用来发出信号，我们最近根据这些发现，我们确定了抑制肿瘤细胞生长和下调 MYC 所必需的。升高 SOX2 通过干扰转录功能下调 MYC 表达促进形成驱动 MYC 所需的关键长程增强子-启动子相互作用的因素该假设将通过两个具体目标进行检验，目标 1 将确定 SOX2 的升高如何改变。 MYC 位点的 3-D 染色质结构将决定升高 SOX2 是否会改变结合。转录因子对 MYC 增强子的影响，改变在活性 MYC 增强子上发现的组蛋白修饰，和/或阻断 MYC 启动子处转录前起始复合物的形成。 SOX2 下调 MYC 将非常重要，因为人们对这些之间的联系知之甚少最终，我们相信我们的研究将导致药物新靶点的发现。根除与癌症复发有关的静止肿瘤细胞。