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The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma

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Listed:
  • Shahid Banday

    (University of Massachusetts Chan Medical School)

  • Alok K. Mishra

    (University of Massachusetts Chan Medical School)

  • Romana Rashid

    (University of Massachusetts Chan Medical School)

  • Tianyi Ye

    (University of Massachusetts Chan Medical School)

  • Amjad Ali

    (University of Massachusetts Chan Medical School)

  • Junhui Li

    (University of Massachusetts Chan Medical School)

  • Jason T. Yustein

    (Emory University)

  • Michelle A. Kelliher

    (University of Massachusetts Chan Medical School)

  • Lihua Julie Zhu

    (University of Massachusetts Chan Medical School
    University of Massachusetts Chan Medical School)

  • Sara K. Deibler

    (University of Massachusetts Chan Medical School)

  • Sunil K. Malonia

    (University of Massachusetts Chan Medical School)

  • Michael R. Green

    (University of Massachusetts Chan Medical School)

Abstract

Ewing sarcoma (ES) is an aggressive bone cancer driven by the oncogenic fusion-protein EWSR1::FLI1, which is not present in normal cells and is therefore an attractive therapeutic target. However, as a transcription factor, EWSR1::FLI1 is considered undruggable. Factors that promote EWSR1::FLI1 expression, and thus whose inhibition would reduce EWSR1::FLI1 protein levels and function, are potential drug targets. Here, using genome-scale CRISPR/Cas9 knockout screening, we identify C1GALT1, a galactosyltransferase required for the biosynthesis of many O-glycoproteins, as a factor that promotes EWSR1::FLI1 expression. We show that C1GALT1 acts by O-glycosylating the pivotal Hedgehog (Hh) signaling component Smoothened (SMO), thereby stabilizing SMO and stimulating the Hh pathway, which we find directly activates EWSR1::FLI1 transcription. Itraconazole, an FDA-approved anti-fungal agent that is known to inhibit C1GALT1, reduces EWSR1::FLI1 levels in ES cell lines and suppresses growth of ES xenografts in mice. Our study reveals a therapeutically targetable mechanism that promotes EWSR1::FLI1 expression and ES tumor growth.

Suggested Citation

  • Shahid Banday & Alok K. Mishra & Romana Rashid & Tianyi Ye & Amjad Ali & Junhui Li & Jason T. Yustein & Michelle A. Kelliher & Lihua Julie Zhu & Sara K. Deibler & Sunil K. Malonia & Michael R. Green, 2025. "The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56632-0
    DOI: 10.1038/s41467-025-56632-0
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    References listed on IDEAS

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    1. Jussi Taipale & James K. Chen & Michael K. Cooper & Baolin Wang & Randall K. Mann & Ljiljana Milenkovic & Matthew P. Scott & Philip A. Beachy, 2000. "Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine," Nature, Nature, vol. 406(6799), pages 1005-1009, August.
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