1. LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma LIN28B Control of EWS-FLI1 Stability
- Author
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Tugba, Keskin, Arnaud, Bakaric, Patricia, Waszyk, Gaylor, Boulay, Matteo, Torsello, Sandrine, Cornaz-Buros, Nadja, Chevalier, Thibaud, Geiser, Patricia, Martin, Angela, Volorio, Sowmya, Iyer, Anupriya, Kulkarni, Igor, Letovanec, Stéphane, Cherix, Gregory M, Cote, Edwin, Choy, Antonia, Digklia, Michael, Montemurro, Ivan, Chebib, Petur G, Nielsen, Angel M, Carcaboso, Jaume, Mora, Raffaele, Renella, Mario L, Suvà, Carlo, Fusco, Paolo, Provero, Miguel N, Rivera, Nicolò, Riggi, and Ivan, Stamenkovic
- Subjects
Oncogene Proteins, Fusion ,Carcinogenesis ,Protein Stability ,Proto-Oncogene Protein c-fli-1 ,RNA Stability ,poor prognosis ,RNA-Binding Proteins ,Sarcoma, Ewing ,Lin28B ,Clone Cells ,Gene Expression Regulation, Neoplastic ,Kinetics ,Mice ,Cell Line, Tumor ,Spheroids, Cellular ,EWS-FLI-1 mRNA stabilization ,Animals ,Humans ,Ewing sarcoma ,therapeutic target ,Cell Self Renewal ,RNA-Binding Protein EWS ,Cell Proliferation - Abstract
Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fueling the search for alternative approaches. Here, we show that the oncofetal RNA-binding protein LIN28B regulates the stability of EWS-FLI1 mRNA in similar to 10% of EwSs. LIN28B depletion in these tumors leads to a decrease in the expression of EWS-FLI1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of LIN28B mimics the effect of LIN28B depletion, suggesting that LIN28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.
- Published
- 2020