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 Giannatale, Giuseppe Maria Milano, Cristiano 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 Angelis, Franco Locatelli and Rossella Rota ()
Additional contact information
Silvia Pomella: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Matteo Cassandri: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Lucrezia D’Archivio: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Antonella Porrazzo: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Cristina Cossetti: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Doris Phelps: UT Health Science Center
Clara Perrone: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Michele Pezzella: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Antonella Cardinale: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Marco Wachtel: University Children’s Hospital
Sara Aloisi: Case Western Reserve University
David Milewski: Genetics Branch, National Cancer Institute, NIH,
Marta Colletti: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Prethish Sreenivas: UT Health Science Center
Zoë S. Walters: Divisions of Molecular Pathology, The Institute of Cancer Research
Giovanni Barillari: University of Rome Tor Vergata
Angela Giannatale: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Giuseppe Maria Milano: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Cristiano Stefanis: Bambino Gesu’ Children’s Hospital, IRCCS
Rita Alaggio: Bambino Gesù Children’s Hospital, IRCCS
Sonia Rodriguez-Rodriguez: City of Hope National Medical Center
Nadia Carlesso: City of Hope National Medical Center
Christopher R. Vakoc: Cold Spring Harbor Laboratory
Enrico Velardi: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Beat W. Schafer: University Children’s Hospital
Ernesto Guccione: Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Susanne A. Gatz: University of Birmingham
Ajla Wasti: Children and Young People’s Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research
Marielle Yohe: National Cancer Institute, NIH
Myron Ignatius: UT Health Science Center
Concetta Quintarelli: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Janet Shipley: Divisions of Molecular Pathology, The Institute of Cancer Research
Lucio Miele: Louisiana State University Health Sciences Center
Javed Khan: Genetics Branch, National Cancer Institute, NIH,
Peter J. Houghton: UT Health Science Center
Francesco Marampon: Sapienza University of Rome
Berkley E. Gryder: Case Western Reserve University
Biagio Angelis: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Franco Locatelli: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
Rossella Rota: Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS

Nature Communications, 2023, vol. 14, issue 1, 1-23

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.

Date: 2023
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DOI: 10.1038/s41467-023-44130-0

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