The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma
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::...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56632-0 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shahid Banday |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-add67afa4bfe4dc9a6523c3d81a60429 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-add67afa4bfe4dc9a6523c3d81a604292025-02-02T12:31:59ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-025-56632-0The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcomaShahid Banday0Alok K. Mishra1Romana Rashid2Tianyi Ye3Amjad Ali4Junhui Li5Jason T. Yustein6Michelle A. Kelliher7Lihua Julie Zhu8Sara K. Deibler9Sunil K. Malonia10Michael R. Green11Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Medicine, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolWinship Cancer Institute and Aflac Cancer and Blood Disorders Center, Emory UniversityDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-025-56632-0 |
| spellingShingle | 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 The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma Nature Communications |
| title | The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma |
| title_full | The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma |
| title_fullStr | The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma |
| title_full_unstemmed | The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma |
| title_short | The O-glycosyltransferase C1GALT1 promotes EWSR1::FLI1 expression and is a therapeutic target for Ewing sarcoma |
| title_sort | o glycosyltransferase c1galt1 promotes ewsr1 fli1 expression and is a therapeutic target for ewing sarcoma |
| url | https://doi.org/10.1038/s41467-025-56632-0 |
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