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Updated: Oct 26, 2025
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma
Bo Kyung A Seong1, Neekesh V Dharia2, Shan Lin1
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Abstract:
Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif-containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared with >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion oncoprotein-specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF-driven cancers.
Insights
Scientists found that TRIM8 protein degrades EWS/FLI, a key driver in Ewing sarcoma. This discovery offers a new way to target fusion oncoproteins in this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Fusion oncoproteins are challenging therapeutic targets in cancer.
- Protein degradation is a novel strategy for targeting these oncoproteins.
- Mechanisms regulating fusion oncoprotein stability are largely unknown.
Purpose of the Study:
- To identify regulators of fusion transcription factor (fusion-TF) stability.
- To explore protein degradation as a therapeutic strategy for fusion-TF-driven cancers.
- To investigate the role of TRIM8 in Ewing sarcoma pathogenesis.
Main Methods:
- CRISPR-Cas9 screening to identify E3 ubiquitin ligases.
- Ubiquitination and protein degradation assays.
- Cancer cell line dependency profiling.
Main Results:
- Tripartite motif-containing 8 (TRIM8) was identified as an E3 ubiquitin ligase.
- TRIM8 ubiquitinates and degrades the EWS/FLI fusion oncoprotein.
- TRIM8 is a selective dependency in Ewing sarcoma cells.
- TRIM8 knockout increases EWS/FLI levels, leading to cell death.
Conclusions:
- Fusion-TF protein stability is tightly regulated.
- TRIM8 is a potential therapeutic target for Ewing sarcoma.
- Targeting oncogene overdose via fusion oncoprotein degradation is a viable strategy.
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