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

TL;DR

Researchers discovered that blocking YOD1 with G5 could disrupt harmful protein interactions and treat a severe type of childhood muscle cancer.

Contribution

The study reveals YOD1 inhibition as a novel therapeutic strategy targeting the PAX-FOXO1/N-Myc feedback loop in rhabdomyosarcoma.

Findings

N-Myc activates PAX-FOXO1 and forms a complex with it, amplifying oncogenic signaling in FP-RMS.

YOD1 stabilizes both PAX-FOXO1 and N-Myc, and its inhibition with G5 reduces tumor growth in FP-RMS.

Blocking YOD1 promotes degradation of both PAX-FOXO1 and N-Myc, disrupting their oncogenic feedback loop.

Abstract

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.

Researchers find PAX-FOXO1 and N-Myc reciprocal regulation amplifies oncogenic signaling in FP-RMS, and blocking YOD1 with G5 could be a new treatment approach.

Figures