한빛사 논문
Dana-Farber Cancer Institute, The Broad Institute of MIT and Harvard
Bo Kyung A. Seong1,2, Neekesh V. Dharia1,2,3, Shan Lin1,2, Katherine A. Donovan4,5, Shasha Chong6,7,10, Amanda Robichaud1, Amy Conway1, Amanda Hamze1, Linda Ross1, Gabriela Alexe1,2, Biniam Adane1,2, Behnam Nabet4,5, Fleur M. Ferguson4,5, Björn Stolte1,8, Emily Jue Wang1, Jialin Sun4,5, Xavier Darzacq6,9, Federica Piccioni2, Nathanael S. Gray4,5,11, Eric S. Fischer4,5, Kimberly Stegmaier1,2,3,12,*
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2The Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA
4Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
5Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
6Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
7Howard Hughes Medical Institute, University of California, Berkeley, CA, USA
8Dr.von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany
9CIRM Center of Excellence, University of California, Berkeley, CA, USA
10Present address: Devision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
11Present address: Chemical and Systems Biology, Chem-H, Stanford Cancer Institute, Stanford Medicine, Stanford, CA, USA
12Lead contact
*Corresponding author
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.
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