Exploiting Oncogenic Chromatin Regulators in Cancer Initiation and Progression

在癌症发生和进展中利用致癌染色质调节因子

• 批准号: 10304789
• 负责人: Usman Hyder
• 金额: $ 3.62万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304789
• 关键词: APC gene; Address; Automobile Driving; Award; Binding; Biological Assay; Biophysics; Cancer Etiology; Cancer Patient; Cell Proliferation; Cells; Chromatin; Clinic; Colorectal Cancer; Complex; Cryoelectron Microscopy; Data; Electron Microscopy; Fusion Oncogene Proteins; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Goals; Histone H2A; Human; Institutes; Knowledge; Lead; Malignant Neoplasms; Modeling; Molecular; Molecular Structure; Mutate; Mutation; Nucleosomes; Oncogenic; Oncoproteins; Patients; Phase; Phenotype; Proteins; Publications; Publishing; Reader; Regulator Genes; Research; Research Project Grants; Role; Running; Site; Structure; Surface; Testing; Therapeutic; Training; Transcriptional Activation; Tumor Suppressor Proteins; Ubiquitin; Up-Regulation; WNT Signaling Pathway; Work; arm; beta catenin; cancer cell; cancer initiation; colon cancer patients; cryogenics; genomic locus; inhibitor/antagonist; lead candidate; loss of function; loss of function mutation; member; mortality; novel; novel strategies; novel therapeutics; programs; promoter; recruit; response; scaffold; small molecule inhibitor; soft tissue; synovial sarcoma; therapeutic target; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis

PROJECT SUMMARY Genetic alterations in cancer cells can cause activation of regulatory factors that bind chromatin at target gene loci to turn on transcription programs that drive tumor initiation and progression. However, despite identification of these oncogenic regulatory factors in multiple tumor types, a gap in this rapidly evolving field is the delineation of molecular mechanisms that open opportunities to target those regulators. Thus, my long-term goal is to define interaction surfaces within chromatin-bound regulators critical for their oncogenic functions. In the F99 phase of this proposal I will focus on the transcription regulator KAP1 and its previously unprecedented role in activating oncogenic WNT signaling in colorectal cancer (CRC). Despite the well- established knowledge that WNT signaling drives CRC transformation and promotes tumor progression, a therapeutic arm that successfully inactivates WNT in CRC has yet to be employed. Potentially addressing this gap in knowledge, my studies have discovered that KAP1 is required for expression of WNT target genes in response to oncogenic WNT stimulation. Importantly, compelling preliminary data support two non-mutually exclusive mechanisms explaining how KAP1 may regulate WNT signaling. First, KAP1 could directly activate WNT by scaffolding key transcriptional machinery to WNT target gene promoters using its chromatin reader module. Second, KAP1 could interact with and regulate β-Catenin stability (the WNT transcription effector). I will test these two models and then evaluate whether perturbing the KAP1–chromatin and/or KAP1–β-Catenin interactions will block WNT-induced CRC phenotypes. In the K00 phase, I will shift focus to another biomedically relevant chromatin regulatory complex (SWI/SNF). SWI/SNF normally remodels nucleosomes on chromatin to activate target gene expression, but its dysregulation in cancer can cause aberrant activation of oncogenic programs. Likewise, in the soft-tissue malignancy Synovial Sarcoma (SS), the transforming genetic alteration is translocation of SS18, a member of SWI/SNF, to the SSX transcription factor. Because SSX, but not SSX18, normally binds modified nucleosomes, SSX abnormally redirects SS18 to a cancer-specific set of genomic sites, causing upregulation of genes that promote tumorigenesis. Despite this mechanistic understanding, the molecular and structural basis of the SS18-SSX– nucleosome interaction remains unclear, and a strategy to target SS18-SSX is currently undefined. To achieve these unmet needs, I will biophysically characterize the SS18-SSX-nucleosome interaction and then identify small-molecule inhibitors that disrupt the SS18-SSX-nucleosome interaction. Finally, I will test lead inhibitor candidates in hallmarks of cancer assays (proliferation and invasion). The training obtained under both phases will fulfill my long-term goal of running my own lab with an emphasis on molecular mechanisms of gene regulation, allowing me to have a positive impact on cancer patients.

项目摘要 癌细胞中的遗传改变可导致调节因子的激活，这些调节因子在靶点结合染色质。 基因位点来开启驱动肿瘤发生和发展的转录程序。但尽管 在多种肿瘤类型中鉴定这些致癌调节因子，在这个快速发展的领域中的空白是 描绘分子机制，打开机会，以针对这些监管机构。因此，我的长期 目的是确定染色质结合的调节器内的相互作用表面，这些调节器对它们的致癌功能至关重要。 在F99阶段的这个建议，我将集中在转录调节KAP 1和它的前 在结直肠癌（CRC）中激活致癌WNT信号传导的前所未有的作用。尽管如此- WNT信号传导驱动CRC转化并促进肿瘤进展的既定知识， 在CRC中成功灭活WNT的治疗臂尚未被采用。为了解决这个问题， 在知识的差距，我的研究发现，KAP 1是需要表达的WNT靶基因， 对致癌WNT刺激的反应。重要的是，令人信服的初步数据支持两个不相互 解释KAP 1如何调节WNT信号传导的独特机制。首先，KAP 1可以直接激活 WNT通过使用其染色质阅读器将关键转录机器支架化到WNT靶基因启动子 module.第二，KAP 1可以与β-Catenin（WNT转录效应子）相互作用并调节β-Catenin的稳定性。我会 测试这两个模型，然后评估是否干扰KAP 1-染色质和/或KAP 1-β-连环蛋白 相互作用将阻断WNT诱导的CRC表型。 在K 00阶段，我将把重点转移到另一个生物医学相关的染色质调控复合物（SWI/SNF）。 SWI/SNF通常重塑染色质上的核小体以激活靶基因的表达，但其失调 会导致致癌程序的异常激活。同样，在软组织恶性肿瘤滑膜中， 肉瘤（SS），转化性遗传改变是SWI/SNF成员SS 18易位到SSX 转录因子因为SSX，而不是SSX 18，通常结合修饰的核小体，SSX异常结合修饰的核小体。 将SS 18重定向到一组癌症特异性基因组位点，导致促进基因表达的基因上调， 肿瘤发生尽管有这种机制上的理解，SS 18-SSX-的分子和结构基础 核小体相互作用仍不清楚，靶向SS 18-SSX的策略目前尚未确定。实现 为了满足这些未满足的需求，我将从生物药理学上表征SS 18-SSX-核小体相互作用，然后鉴定 破坏SS 18-SSX-核小体相互作用的小分子抑制剂。最后，我将测试铅抑制剂 癌症检测标志（增殖和侵袭）的候选物。 在这两个阶段获得的培训将实现我重点运营自己实验室的长期目标 基因调控的分子机制，让我对癌症患者产生积极的影响。