LIN28B Underlies the Pathogenesis of a Subclass of Ewing Sarcoma LIN28B Control of EWS-FLI1 Stability

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 approac...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2020-03, Vol.30 (13), p.4567
Main Authors: Keskin, Tugba, Bakaric, Arnaud, Waszyk, Patricia, Boulay, Gaylor, Torsello, Matteo, Cornaz-Buros, Sandrine, Chevalier, Nadja, Geiser, Thibaud, Martin, Patricia, Volorio, Angela, Iyer, Sowmya, Kulkarni, Anupriya, Letovanec, Igor, Cherix, Stéphane, Cote, Gregory M, Choy, Edwin, Digklia, Antonia, Montemurro, Michael, Chebib, Ivan, Nielsen, Petur G, Carcaboso, Angel M, Mora, Jaume, Renella, Raffaele, Suvà, Mario L, Fusco, Carlo, Provero, Paolo, Rivera, Miguel N, Riggi, Nicolò, Stamenkovic, Ivan
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis - genetics
Carcinogenesis - pathology
Cell Line, Tumor
Cell Proliferation
Cell Self Renewal
Clone Cells
Gene Expression Regulation, Neoplastic
Humans
Kinetics
Mice
Oncogene Proteins, Fusion - metabolism
Protein Stability
Proto-Oncogene Protein c-fli-1 - metabolism
RNA Stability
RNA-Binding Protein EWS - metabolism
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Sarcoma, Ewing - genetics
Sarcoma, Ewing - pathology
Spheroids, Cellular - pathology
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Summary: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 ~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.
ISSN:2211-1247
DOI:10.1016/j.celrep.2019.12.053