MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting.
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
Nature communications 2023 Dec 15Rhabdomyosarcomas (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. © 2023. The Author(s).
Citation
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. MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting. Nature communications. 2023 Dec 15;14(1):8373
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PMID: 38102140
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