These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


PUBMED FOR HANDHELDS

Search MEDLINE/PubMed


  • Title: TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma.
    Author: Seong BKA, 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 EJ, Sun J, Darzacq X, Piccioni F, Gray NS, Fischer ES, Stegmaier K.
    Journal: Cancer Cell; 2021 Sep 13; 39(9):1262-1278.e7. PubMed ID: 34329586.
    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.
    [Abstract] [Full Text] [Related] [New Search]