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Updated: Jan 8, 2026

Tumorsphere Derivation and Treatment from Primary Tumor Cells Isolated from Mouse Rhabdomyosarcomas
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Therapeutic targeting of YOD1 disrupts the PAX-FOXO1/N-Myc feedback loop in rhabdomyosarcoma

Wenwen Ying1,2, Jiayi Yu3, Xiaomin Wang1

  • 1Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, and.

JCI Insight
|December 16, 2025
PubMed

Insights

N-Myc amplifies oncogenic signaling in fusion-positive rhabdomyosarcoma (FP-RMS) by forming a feedback loop with PAX3-FOXO1. Inhibiting YOD1, a deubiquitinating enzyme, reduces both proteins and suppresses FP-RMS growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Fusion-positive rhabdomyosarcoma (FP-RMS) driven by PAX3-FOXO1 has a poor prognosis.
  • The oncogenic mechanisms and therapeutic targets of PAX3-FOXO1 are not fully understood.

Purpose of the Study:

  • To elucidate the oncogenic role of N-Myc in FP-RMS.
  • To identify novel therapeutic strategies targeting the PAX3-FOXO1 pathway.

Main Methods:

  • Investigated the interaction between PAX3-FOXO1 and N-Myc using molecular biology techniques.
  • Identified YOD1 as a key regulator of PAX3-FOXO1 and N-Myc stability.
  • Utilized in vitro and in vivo models to assess the therapeutic potential of YOD1 inhibition.

Main Results:

  • Discovered that N-Myc reciprocally activates PAX3-FOXO1, forming a critical positive feedback loop for FP-RMS malignancy.
  • Identified YOD1 as a deubiquitinating enzyme stabilizing both PAX3-FOXO1 and N-Myc.
  • Demonstrated that YOD1 inhibition (using G5) suppressed FP-RMS growth by promoting degradation of PAX3-FOXO1 and N-Myc.

Conclusions:

  • YOD1 promotes FP-RMS progression by stabilizing the PAX3-FOXO1-N-Myc feedback loop.
  • YOD1 inhibition represents a promising therapeutic strategy for FP-RMS, concurrently targeting both oncogenic proteins.
Keywords:
Cell biologyOncologyPharmacologyUbiquitin-proteosome system

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