학술논문
MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
Document Type
article
Author
Silvia Pomella; Matteo Cassandri; Lucrezia D’Archivio; Antonella Porrazzo; Cristina Cossetti; Doris Phelps; Clara Perrone; Michele Pezzella; Antonella Cardinale; Marco Wachtel; Sara Aloisi; David Milewski; Marta Colletti; Prethish Sreenivas; Zoë S. Walters; Giovanni Barillari; Angela Di Giannatale; Giuseppe Maria Milano; Cristiano De Stefanis; Rita Alaggio; Sonia Rodriguez-Rodriguez; Nadia Carlesso; Christopher R. Vakoc; Enrico Velardi; Beat W. Schafer; Ernesto Guccione; Susanne A. Gatz; Ajla Wasti; Marielle Yohe; Myron Ignatius; Concetta Quintarelli; Janet Shipley; Lucio Miele; Javed Khan; Peter J. Houghton; Francesco Marampon; Berkley E. Gryder; Biagio De Angelis; Franco Locatelli; Rossella Rota
Source
Nature Communications, Vol 14, Iss 1, Pp 1-23 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
Abstract Rhabdomyosarcomas (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.