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

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. NielsenAngel M. Carcaboso, Jaume Mora, Raffaele Renella, Mario L. Suvà, Carlo Fusco, Paolo Provero, Miguel N. Rivera, Nicolò Riggi, Ivan Stamenkovic

Research output: Contribution to journalArticlepeer-review

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 ~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.

Original languageEnglish
Pages (from-to)4567-4583.e5
JournalCell Reports
Volume30
Issue number13
DOIs
Publication statusPublished - Mar 31 2020

Keywords

  • Ewing sarcoma
  • EWS-FLI-1 mRNA stabilization
  • Lin28B
  • poor prognosis
  • therapeutic target

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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