Related Experiment Video

Updated: Jul 8, 2025

Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
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Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas

Published on: September 13, 2019

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

Silvia Pomella1,2, Matteo Cassandri1,3, Lucrezia D'Archivio1

  • 1Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Roma, Italy.

Nature Communications
|December 15, 2023
PubMed

Insights

We identified SKP2 as a key driver in fusion-negative rhabdomyosarcomas (FN-RMS). Targeting SKP2 or NEDDylation shows promise for treating this pediatric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Rhabdomyosarcomas (RMS) are pediatric cancers with distinct subtypes, including Fusion-Negative (FN)-RMS.
  • While MYOD is crucial for RMS survival, it doesn't induce differentiation.
  • FN-RMS often harbors RAS pathway mutations.

Purpose of the Study:

  • To identify novel pro-tumorigenic drivers in FN-RMS.
  • To elucidate the role of SKP2 in FN-RMS pathogenesis.
  • To explore therapeutic vulnerabilities in FN-RMS.

Main Methods:

  • Investigated SKP2 expression and regulation by MYOD in RMS.
  • Assessed the impact of SKP2 depletion on cell cycle, differentiation, and stemness.
  • Utilized the NEDDylation inhibitor MLN4924 to study its effects in FN-RMS models.
  • Evaluated in vivo tumor growth after SKP2 manipulation.

Main Results:

  • Discovered SKP2 overexpression in RMS, driven by MYOD binding to an intronic enhancer.
  • Demonstrated that SKP2 promotes cell cycle progression and inhibits differentiation by targeting p27Kip1 and p57Kip2.
  • SKP2 depletion reactivated myogenic programs, reduced stemness, and inhibited tumor growth.
  • MLN4924 mimicked the effects of SKP2 inhibition.

Conclusions:

  • Established a critical MYOD-SKP2 axis linking transcriptional and post-translational regulation in FN-RMS tumorigenesis.
  • Identified SKP2 as a crucial oncogenic driver in FN-RMS.
  • Highlighted NEDDylation inhibition as a potential therapeutic strategy for FN-RMS.

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