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

Feb 03, 2025

Experts: 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

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.
© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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ABOUT THE EXPERTS

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

Shahid Banday

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. shahidkhursheed.banday@umassmed.edu.

Alok K Mishra

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Romana Rashid

Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Tianyi Ye

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Amjad Ali

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Junhui Li

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Jason T Yustein

Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, 30322, USA.

Michelle A Kelliher

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Lihua Julie Zhu

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Program in Molecular Medicine and Department of Genomics and Computational Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Sara K Deibler

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Sunil K Malonia

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. sunil.malonia@umassmed.edu.

Michael R Green

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.