2. Academic Validation
  3. The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma

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

  • Nat Commun. 2025 Feb 2;16(1):1267. doi: 10.1038/s41467-025-56632-0.
Shahid Banday 1,  Alok K Mishra 2,  Romana Rashid 3,  Tianyi Ye 2,  Amjad Ali 2,  Junhui Li 2,  Jason T Yustein 4,  Michelle A Kelliher 2,  Lihua Julie Zhu 2 5,  Sara K Deibler 2,  Sunil K Malonia 6,  Michael R Green 2
Affiliations

Affiliations

  • 1 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. shahidkhursheed.banday@umassmed.edu.
  • 2 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • 3 Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • 4 Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, 30322, USA.
  • 5 Program in Molecular Medicine and Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
  • 6 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. sunil.malonia@umassmed.edu.
PMID: 39894896 DOI: 10.1038/s41467-025-56632-0
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-160109
    98.39%, O-glycan Inhibitor