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Mechanisms underlying USP1-mediated bypass of EWS-FLI1 oncogene-induced replication stress in Ewing sarcoma

USP1介导的EWS-FLI1癌基因诱导的尤文肉瘤复制应激旁路的机制

基本信息

批准号：
10446807
负责人：
GARGI GHOSAL
金额：
$ 35.11万
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：
2022-08-05 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446807
关键词：
Apoptosis Basic Science Bypass Cell Aging Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Death Cell Line Cell Maintenance Cell Proliferation Cell physiology Cells ChIP-seq Childhood Chromosomal translocation Chromosome 11 Chromosome 22 DNA DNA Damage DNA Repair DNA biosynthesis DNA-protein crosslink Data Deubiquitination Development Disease Progression E2F transcription factors EWSR1 gene Epigenetic Process Ewings sarcoma FLI1 gene Family Fiber Gene Expression Gene Fusion Generations Genes Genetic Transcription Genome Genome Stability Genomic Instability Growth HELLS gene Histones In Vitro Lysine Malignant Bone Neoplasm Maps Mediating Mesenchymal Stem Cells Molecular Normal Cell Oncogenes Oncogenic Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenocopy Proteins Regulation Role S phase Site Testing Treatment Efficacy Ubiquitin Ubiquitination Xenograft Model base biological adaptation to stress bone cancer cell cell growth chemotherapy chromatin remodeling comparative epigenetic regulation genome wide methylation genome-wide analysis improved in vivo inhibitor insight knock-down methylation pattern mutant new therapeutic target novel overexpression repaired replication stress response sarcoma small molecule standard of care stem cells t(11 22)(q24 q12)targeted treatment transcription factor transcriptome sequencing treatment strategy tumor tumor growth tumorigenesis ubiquitin-protein ligase ubiquitin-specific protease

项目摘要

PROJECT SUMMARY Replication stress leading to genome instability is an early driver of tumorigenesis and has been associated with overexpression of oncogenes. In normal cells, activation of the DNA damage response (DDR) pathway serves as a barrier to tumorigenesis leading to cell cycle arrest inducing cellular senescence or cell death in response to high burden of genome instability. However, in cancer cells upon oncogene-induced replication stress the protective barrier of DDR, cell death and senescence is bypassed leading to uncontrolled cell proliferation. Therefore, deciphering the mechanisms that bypass oncogene-induced replication stress and senescence will help understand the basic science underlying disease progression and will identify new targets for therapy. Ewing sarcoma (EWS) is driven by a chromosomal translocation and in-frame gene fusion between EWSR1 and ETS family of transcription factors. In majority of the EWS cases, the chromosomal translocation results in the generation of EWS-FLI1 oncogene. EWS-FLI1 functions as an aberrant transcription factor that drives the development and progression of EWS. Expression of EWS-FLI1 oncogene leads to oncogene-induced replication stress and genome instability. However, the molecular mechanism underlying bypass of EWS-FLI1 oncogene-induced replication stress response pathways is largely unknown. Our preliminary data shows that USP1 deubiquitinase is overexpressed in EWS cell lines and tumors. USP1 regulates DDR and is required for genome stability and stem cell maintenance. We find that USP1 expression is regulated by EWS-FLI1 in EWS. Importantly, inhibition of USP1 activity using small molecule USP1 inhibitors resulted in growth arrest of EWS cell lines indicating that USP1 expression and activity is important for EWS cell proliferation and progression. Notably, USP1 depletion led to a decrease in the levels of HELLS chromatin remodeling protein. The function of USP1 or HELLS in EWS pathogenesis has not been investigated. In this study, we will examine the regulation of HELLS by USP1 deubiquitinase (Aim 1), determine the mechanism by which USP1 promotes EWS cell proliferation (Aim 2), and determine the effect of USP1 knockdown on EWS tumor formation in vivo and the efficacy of USP1 inhibition in combination with chemotherapeutic drugs at suppressing EWS cell proliferation (Aim 3). Successful completion of this study will unravel novel mechanistic insights into USP1 mediated bypass of EWS-FLI1 oncogene-induced replication stress and help evaluate USP1 targeted treatment strategies for EWS.

项目总结