Therapeutic targeting of YOD1 disrupts the PAX-FOXO1/N-Myc feedback loop in rhabdomyosarcoma

作者：Wen-wen Ying, Jiayi Yu, Xiaomin Wang, Jiayi Liu, Boyu Deng, Xuejing Shao, Jinhu Wang, Ting Tao, Ji Cao, Qiaojun He, Bo Yang, Yifan Chen, Meidan Ying · 发表于：JCI Insight · 年份：2025 · DOI：10.1172/jci.insight.193221 · 被引用次数：2 · 研究领域：FOXO transcription factor regulation、Hippo pathway signaling and YAP/TAZ、Sarcoma Diagnosis and Treatment

Fusion-positive rhabdomyosarcoma (FP-RMS), driven by PAX-FOXO1 fusion oncoproteins, represents the subtype of RMS with the poorest prognosis. However, the oncogenic mechanisms and therapeutic strategies of PAX-FOXO1 remain incompletely understood. Here, we discovered that N-Myc, in addition to being a classic downstream target of PAX-FOXO1, can also activate its expression and form a transcriptional complex with PAX-FOXO1, thereby markedly amplifying oncogenic signaling. The reciprocal transcriptional activation of PAX3-FOXO1 and N-Myc is critical for FP-RMS malignancy. We further identified YOD1 as a deubiquitinating enzyme that stabilizes both PAX-FOXO1 and N-Myc. Knocking down YOD1 or inhibiting it with G5 could suppress FP-RMS growth both in vitro and in vivo, through promoting the degradation of both PAX-FOXO1 and N-Myc. Collectively, our results identify that YOD1 promotes RMS progression by regulating the PAX3-FOXO1/N-Myc positive feedback loop, and highlight YOD1 inhibition as a promising therapeutic strategy that concurrently reduces the levels of both oncogenic proteins.