dc.contributor.author | Pomella, S | |
dc.contributor.author | Cassandri, M | |
dc.contributor.author | D'Archivio, L | |
dc.contributor.author | Porrazzo, A | |
dc.contributor.author | Cossetti, C | |
dc.contributor.author | Phelps, D | |
dc.contributor.author | Perrone, C | |
dc.contributor.author | Pezzella, M | |
dc.contributor.author | Cardinale, A | |
dc.contributor.author | Wachtel, M | |
dc.contributor.author | Aloisi, S | |
dc.contributor.author | Milewski, D | |
dc.contributor.author | Colletti, M | |
dc.contributor.author | Sreenivas, P | |
dc.contributor.author | Walters, ZS | |
dc.contributor.author | Barillari, G | |
dc.contributor.author | Di Giannatale, A | |
dc.contributor.author | Milano, GM | |
dc.contributor.author | De Stefanis, C | |
dc.contributor.author | Alaggio, R | |
dc.contributor.author | Rodriguez-Rodriguez, S | |
dc.contributor.author | Carlesso, N | |
dc.contributor.author | Vakoc, CR | |
dc.contributor.author | Velardi, E | |
dc.contributor.author | Schafer, BW | |
dc.contributor.author | Guccione, E | |
dc.contributor.author | Gatz, SA | |
dc.contributor.author | Wasti, A | |
dc.contributor.author | Yohe, M | |
dc.contributor.author | Ignatius, M | |
dc.contributor.author | Quintarelli, C | |
dc.contributor.author | Shipley, J | |
dc.contributor.author | Miele, L | |
dc.contributor.author | Khan, J | |
dc.contributor.author | Houghton, PJ | |
dc.contributor.author | Marampon, F | |
dc.contributor.author | Gryder, BE | |
dc.contributor.author | De Angelis, B | |
dc.contributor.author | Locatelli, F | |
dc.contributor.author | Rota, R | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-03-13T10:42:06Z | |
dc.date.available | 2024-03-13T10:42:06Z | |
dc.date.issued | 2023-12-15 | |
dc.identifier | ARTN 8373 | |
dc.identifier | 10.1038/s41467-023-44130-0 | |
dc.identifier.citation | Nature Communications, 2023, 14 (1), pp. 8373 - | en_US |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6189 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-023-44130-0 | |
dc.identifier.doi | 10.1038/s41467-023-44130-0 | |
dc.description.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. | |
dc.format | Electronic | |
dc.format.extent | 8373 - | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | NATURE PORTFOLIO | en_US |
dc.relation.ispartof | Nature Communications | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Humans | |
dc.subject | Carcinogenesis | |
dc.subject | Cell Line, Tumor | |
dc.subject | Rhabdomyosarcoma | |
dc.subject | Transcription Factors | |
dc.subject | Cell Transformation, Neoplastic | |
dc.subject | Cell Differentiation | |
dc.title | MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-11-30 | |
dc.date.updated | 2024-03-13T10:41:39Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s41467-023-44130-0 | en_US |
rioxxterms.licenseref.startdate | 2023-12-15 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38102140 | |
pubs.issue | 1 | |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Sarcoma Molecular Pathology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Sarcoma Molecular Pathology | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41467-023-44130-0 | |
pubs.volume | 14 | |
icr.researchteam | Sarcoma Mol Pathol | en_US |
dc.contributor.icrauthor | Shipley, Janet | |
icr.provenance | Deposited by Mr Arek Surman (impersonating Dr Nicolo Battisti) on 2024-03-13. Deposit type is initial. No. of files: 1. Files: MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57supKip2sup .pdf | |