TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Seong, Bo Kyung A.; Dharia, Neekesh V.; Lin, Shan; Donovan, Katherine A.; Chong, Shasha; Robichaud, Amanda; Conway, Amy; Hamze, Amanda; Ross, Linda; Alexe, Gabriela; Adane, Biniam; Nabet, Behnam; Ferguson, Fleur M.; Stolte, Bjorn; Wang, Emily Jue; Sun, Jialin; Darzacq, Xavier; Piccioni, Federica; Gray, Nathanael S.; Fischer, Eric S. und Stegmaier, Kimberly (2021): TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma. In: Cancer Cell, Bd. 39, Nr. 9: S. 1262-1278

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. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1535-6108
• Sprache: Englisch