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Updated: Sep 11, 2025
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Arginine methylation regulates Ewing sarcoma cell viability in a EWSR1::FLI1 dependent manner and provides a
Ciara M Ward1, Charles Brockwell1, Gavin S McNee2
1Department of Cancer and Genomic Sciences, College of Medical and Health Sciences, University of Birmingham, Birmingham, United Kingdom.
Introduction:
Ewing sarcoma is a rare type of cancer arising from bone and soft tissues mainly affecting children and young adults. Treatments include intensive chemotherapy, surgery and radiotherapy, however more than 30% of patients die from the disease. Direct drug targeting of EWS-FLI1 remains a significant challenge, therefore new approaches are urgently required.
Methods:
Analysis of PRMT1 and PRMT5 transcript expression using the R2 platform focusing on the Filion dataset of sarcomas that includes Ewing sarcoma patients alongside other fusion-positive sarcomas and breast and lung cancer datasets. Immunoblotting across a panel of Ewing sarcoma cell lines detected PRMT1 and PRMT5 expression and associated activity. Cell viability assay after PRMT inhibition, with and without olaparib, were conducted by trypan blue exclusion and MTT assay. DNA damage was detected by immunofluorescence staining for markers of DNA damage (γH2AX) and double-strand breaks (53BP1).
Results:
We show that the expression and activity of the arginine methyltransferases PRMT1 and PRMT5 are elevated in Ewing sarcoma and that inhibition of PRMT1 or PRMT5 with pre-clinical inhibitors leads to growth arrest and apoptosis that is dependent on the expression of the driver oncogene EWSR1::FLI1. Mechanically, we show that PRMT1 and PRMT5 inhibitors promote DNA damage, and that PRMT5 inhibitors synergise with the PARP inhibitor olaparib to induce elevated DNA damage and reduced cell viability.
Discussion:
Our study implies that PRMT1/PRMT5 are important mediators of EWSR1::FLI1 oncogenicity and that drug targeting PRMT1/PRMT5 in combination with DNA damaging chemotherapies could be an effective therapeutic strategy for the treatment of ES patients.
Insights
Targeting PRMT1 and PRMT5 shows promise for Ewing sarcoma treatment. Inhibiting these enzymes halts cancer growth and induces cell death, offering a new therapeutic avenue for this rare bone cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Ewing sarcoma is a rare bone and soft tissue cancer affecting children and young adults.
- Current treatments like chemotherapy, surgery, and radiotherapy have limited efficacy, with over 30% mortality.
- Targeting the oncogenic driver EWSR1::FLI1 directly remains a significant challenge, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of arginine methyltransferases PRMT1 and PRMT5 in Ewing sarcoma pathogenesis.
- To evaluate the therapeutic potential of inhibiting PRMT1 and PRMT5 in Ewing sarcoma.
- To explore the synergistic effects of PRMT inhibition with DNA damaging agents.
Main Methods:
- Analysis of PRMT1 and PRMT5 transcript expression in sarcoma datasets, including Ewing sarcoma.
- Assessment of PRMT1 and PRMT5 protein expression and activity in Ewing sarcoma cell lines.
- Cell viability assays following PRMT inhibition, alone and in combination with olaparib.
- Detection of DNA damage markers (γH2AX, 53BP1) after PRMT inhibition.
Main Results:
- PRMT1 and PRMT5 expression and activity are elevated in Ewing sarcoma.
- Inhibition of PRMT1 or PRMT5 leads to growth arrest and apoptosis, dependent on EWSR1::FLI1.
- PRMT1/PRMT5 inhibition induces DNA damage in Ewing sarcoma cells.
- PRMT5 inhibition synergizes with olaparib to enhance DNA damage and reduce cell viability.
Conclusions:
- PRMT1 and PRMT5 are crucial mediators of EWSR1::FLI1 oncogenicity in Ewing sarcoma.
- Targeting PRMT1/PRMT5, particularly in combination with DNA-damaging therapies, represents a promising therapeutic strategy for Ewing sarcoma.
- This approach offers a potential new avenue to improve treatment outcomes for patients with this challenging cancer.
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