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: 10473739
• 负责人: Usman Hyder
• 金额: $ 3.54万
• 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/10473739
• 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; 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; 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.

项目总结