Dataset Information

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57^Kip2 targeting.

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 p27^Kip1 and p57^Kip2, 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.

SUBMITTER: Pomella S

PROVIDER: S-EPMC10724275 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57<sup>Kip2</sup> targeting.

Pomella Silvia S Cassandri Matteo M D'Archivio Lucrezia L Porrazzo Antonella A Cossetti Cristina C Phelps Doris D Perrone Clara C Pezzella Michele M Cardinale Antonella A Wachtel Marco M Aloisi Sara S Milewski David D Colletti Marta M Sreenivas Prethish P Walters Zoë S ZS Barillari Giovanni G Di Giannatale Angela A Milano Giuseppe Maria GM De Stefanis Cristiano C Alaggio Rita R Rodriguez-Rodriguez Sonia S Carlesso Nadia N Vakoc Christopher R CR Velardi Enrico E Schafer Beat W BW Guccione Ernesto E Gatz Susanne A SA Wasti Ajla A Yohe Marielle M Ignatius Myron M Quintarelli Concetta C Shipley Janet J Miele Lucio L Khan Javed J Houghton Peter J PJ Marampon Francesco F Gryder Berkley E BE De Angelis Biagio B Locatelli Franco F Rota Rossella R

Nature communications 20231215 1

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 int ...[more]

PMID: 38102140

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Project description:BackgroundThe syncytiotrophoblast (SCT) layer in the placenta serves as a crucial physical barrier separating maternal-fetal circulation, facilitating essential signal and substance exchange between the mother and fetus. Any abnormalities in its formation or function can result in various maternal syndromes, such as preeclampsia. The transition of proliferative villous cytotrophoblasts (VCT) from the mitotic cell cycle to the G0 phase is a prerequisite for VCT differentiation and their fusion into SCT. The imprinting gene P57Kip2, specifically expressed in intermediate VCT capable of fusion, plays a pivotal role in driving this key event. Moreover, aberrant expression of P57Kip2 has been linked to pathological placental conditions and adverse fetal outcomes.MethodsValidation of STK40 interaction with P57Kip2 using rigid molecular simulation docking and co-immunoprecipitation. STK40 expression was modulated by lentivirus in BeWo cells, and the effect of STK40 on trophoblast fusion was assessed by real-time quantitative PCR, western blot, immunofluorescence, and cell viability and proliferation assays. Co-immunoprecipitation, transcriptome sequencing, and western blot were used to determine the potential mechanisms by which STK40 regulates P57Kip2.ResultsIn this study, STK40 has been identified as a novel interacting protein with P57Kip2, and its expression is down-regulated during the fusion process of trophoblast cells. Overexpressing STK40 inhibited cell fusion in BeWo cells while stimulating mitotic cell cycle activity. Further experiments indicated that this effect is attributed to its specific binding to the CDK-binding and the Cyclin-binding domains of P57Kip2, mediating the E3 ubiquitin ligase COP1-mediated ubiquitination and degradation of P57Kip2. Moreover, abnormally high expression of STK40 might significantly contribute to the occurrence of preeclampsia.ConclusionsThis study offers new insights into the role of STK40 in regulating the protein-level homeostasis of P57Kip2 during placental development.

Dataset Information

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57^Kip2 targeting.

Publications

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57<sup>Kip2</sup> targeting.

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Dataset Information

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

Publications

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57&lt;sup&gt;Kip2&lt;/sup&gt; targeting.

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OmicsDI is part of the ELIXIR infrastructure

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MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57^Kip2 targeting.

MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57<sup>Kip2</sup> targeting.