MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
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Published:2023-12-15
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Pomella Silvia, Cassandri Matteo, D’Archivio Lucrezia, Porrazzo Antonella, Cossetti Cristina, Phelps Doris, Perrone Clara, Pezzella MicheleORCID, Cardinale Antonella, Wachtel MarcoORCID, Aloisi Sara, Milewski DavidORCID, Colletti Marta, Sreenivas PrethishORCID, Walters Zoë S., Barillari Giovanni, Di Giannatale Angela, Milano Giuseppe MariaORCID, De Stefanis Cristiano, Alaggio Rita, Rodriguez-Rodriguez SoniaORCID, Carlesso NadiaORCID, Vakoc Christopher R.ORCID, Velardi Enrico, Schafer Beat W.ORCID, Guccione ErnestoORCID, Gatz Susanne A.ORCID, Wasti Ajla, Yohe Marielle, Ignatius MyronORCID, Quintarelli Concetta, Shipley JanetORCID, Miele LucioORCID, Khan JavedORCID, Houghton Peter J., Marampon Francesco, Gryder Berkley E.ORCID, De Angelis BiagioORCID, Locatelli FrancoORCID, Rota RossellaORCID
Abstract
AbstractRhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.
Funder
Associazione Italiana per la Ricerca sul Cancro Ministero della Salute Alleanza Contro il Cancro (ACC) Italian Network-Working Group Sarcomas V Foundation for Cancer Research DOD’s Convergent Science Virtual Cancer Center; Reign in Sarcoma
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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