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

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 () and Michael R. Green
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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
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

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56632-0

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