Journal
CANCER CELL
Volume 39, Issue 9, Pages 1262-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2021.07.003
Keywords
-
Categories
Funding
- National Cancer Institute [R35 CA210030, R01 CA204915, U54 CA231637]
- St. Baldrick's Foundation Robert J. Arceci Innovation Award
- Brian MacIsaac Sarcoma Foundation
- Department of Defense PRCRP Horizon Award [CA181249]
- Julia's Legacy of Hope St. Baldrick's Foundation Fellowship
- American Cancer Society Postdoctoral Fellowship [PF-17-010-01-CDD]
- Katherine L. and Steven C. Pinard Research Fund
- Hale Center for Pancreatic Cancer
- [U54 CA231641-01]
- CDMRP [1102272, CA181249] Funding Source: Federal RePORTER
Ask authors/readers for more resources
Fusion-transcription factors (fusion-TFs) are difficult to therapeutically target, but recent research has discovered TRIM8 as a selective E3 ubiquitin ligase for degrading a driver fusion-TF in Ewing sarcoma. Knocking out TRIM8 leads to increased levels of the fusion TF, EWS/FLI, providing a potential strategy for exploiting oncogene overdose in Ewing sarcoma and other fusion-TF driven cancers.
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. Themechanisms 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available