|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Seong, BKyung A, Dharia, NV, Lin, S, Donovan, KA, Chong, S, Robichaud, A, Conway, A, Hamze, A, Ross, L, Alexe, G, Adane, B, Nabet, B, Ferguson, FM, Stolte, B, Wang, EJue, Sun, J, Darzacq, X, Piccioni, F, Gray, NS, Fischer, ES, Stegmaier, K|
|Date Published||2021 Jul 22|
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.
|Alternate Journal||Cancer Cell|