MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting.
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ICR Authors
Authors
Pomella, S
Cassandri, M
D'Archivio, L
Porrazzo, A
Cossetti, C
Phelps, D
Perrone, C
Pezzella, M
Cardinale, A
Wachtel, M
Aloisi, S
Milewski, D
Colletti, M
Sreenivas, P
Walters, ZS
Barillari, G
Di Giannatale, A
Milano, GM
De Stefanis, C
Alaggio, R
Rodriguez-Rodriguez, S
Carlesso, N
Vakoc, CR
Velardi, E
Schafer, BW
Guccione, E
Gatz, SA
Wasti, A
Yohe, M
Ignatius, M
Quintarelli, C
Shipley, J
Miele, L
Khan, J
Houghton, PJ
Marampon, F
Gryder, BE
De Angelis, B
Locatelli, F
Rota, R
Cassandri, M
D'Archivio, L
Porrazzo, A
Cossetti, C
Phelps, D
Perrone, C
Pezzella, M
Cardinale, A
Wachtel, M
Aloisi, S
Milewski, D
Colletti, M
Sreenivas, P
Walters, ZS
Barillari, G
Di Giannatale, A
Milano, GM
De Stefanis, C
Alaggio, R
Rodriguez-Rodriguez, S
Carlesso, N
Vakoc, CR
Velardi, E
Schafer, BW
Guccione, E
Gatz, SA
Wasti, A
Yohe, M
Ignatius, M
Quintarelli, C
Shipley, J
Miele, L
Khan, J
Houghton, PJ
Marampon, F
Gryder, BE
De Angelis, B
Locatelli, F
Rota, R
Document Type
Journal Article
Date
2023-12-15
Date Accepted
2023-11-30
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.
Citation
Nature Communications, 2023, 14 (1), pp. 8373 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Sarcoma Mol Pathol