MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting

Pomella, Silvia, Cassandri, Matteo, D'Archivio, Lucrezia, Porrazzo, Antonella, Cossetti, Cristina, Phelps, Doris, Perrone, Clara, Pezzella, Michele, Cardinale, Antonella, Wachtel, Marco, Aloisi, Sara, Milewski, David, Colletti, Marta, Sreenivas, Prethish, Walters, Zoë S, Barillari, Giovanni, Di Giannatale, Angela, Milano, Giuseppe Maria, De Stefanis, Cristiano, Alaggio, Rita, Rodriguez-Rodriguez, Sonia, Carlesso, Nadia, Vakoc, Christopher R, Velardi, Enrico, Schafer, Beat W, Guccione, Ernesto, Gatz, Susanne A, Wasti, Ajla, Yohe, Marielle, Ignatius, Myron, Quintarelli, Concetta, Shipley, Janet, Miele, Lucio, Khan, Javed, Houghton, Peter J, Marampon, Francesco, Gryder, Berkley E, De Angelis, Biagio, Locatelli, Franco, Rota, Rossella (December 2023) MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting. Nature Communications, 14 (1). p. 8373. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell differentiation organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > differentiation organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types diseases & disorders > cancer > cancer types > rhabdomyosarcoma diseases & disorders > cancer > cancer types > sarcoma bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R.
Communities:	CSHL labs > Vakoc lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	15 December 2023
Date Deposited:	02 Jan 2024 13:52
Last Modified:	30 Apr 2024 17:36
PMCID:	PMC10724275
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41373

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