Transcription, R-Loops, and RNA Splicing in Ewing Sarcoma
Abstract
Ewing sarcoma (EwS) is an aggressive pediatric bone and soft tissue cancer driven primarily by the EWS-FLI1 fusion oncogene. EWS-FLI1 acts as a transcription factor and also interferes with normal regulation of transcription and transcription-associated RNA processing. We hypothesized that EWS-FLI1 driven hyper-activation of transcription causes a targetable dependence on RNA splicing in Ewing sarcoma. The specific aims of the project are to 1) determine the mechanistic relationship between EWS-FLI1-driven transcription, R-loops, and splicing vulnerabilities in EwS, and 2) establish splicing as a therapeutic target in EwS. We tested the effect of depletion of key splicing factors and found an increased sensitivity in EwS compared to control cells. This was partially rescued by depleting EWS-FLI1 or by overexpressing RNASEH1, which degrades R-loops. EwS cells were extremely sensitive to splicing inhibition, which showed synergy with multiple chemotherapeutic agents. Splicing inhibition also caused cell cycle arrest and induced apoptosis. This work provides novel insight into transcription regulation and its dysregulation by EWS-FLI1. In addition, our results point to RNA splicing as a potential new therapeutic target in Ewing sarcoma, which has the potential to benefit all Ewing sarcoma patients, especially those with chemo-resistant disease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1201612
Entities
People
- Liesl A Lawrence
Organizations
- University of Texas at Austin