Document Type
Article
Publication Date
12-15-2023
Publication Title
Nature Communications
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.
PubMed ID
38102140
Volume
14
Issue
1
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
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.; and Miele, Lucio, "MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57KIP2 targeting" (2023). School of Medicine Faculty Publications. 1852.
https://digitalscholar.lsuhsc.edu/som_facpubs/1852
Included in
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Comments
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