NeuroD1-USP1-MYCN axis drives tumor progression in neuroblastoma.
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BACKGROUND: Neuroblastoma, originating from the sympathetic neural crest, is the most prevalent extracranial solid tumor in children. Amplification of MYCN is a widely recognized indicator of poor prognosis in neuroblastoma. However, the structural properties of the N-Myc protein encoded by MYCN have impeded the development of direct inhibitors with favorable drug-like properties. This study aimed to investigate the upstream regulatory mechanisms of N-Myc stabilization in neuroblastoma and explore potential therapeutic strategies targeting these mechanisms. METHODS: The regulatory role of NeuroD1 in neuroblastoma was evaluated through in vitro and in vivo experiments. Mechanistic studies were performed to examine the effects of NeuroD1 knockdown on N-Myc ubiquitination and degradation. Transcriptional target screening through RNAseq and ChIPseq was conducted to identify downstream effectors of NeuroD1, and the interaction between USP1 and N-Myc was assessed by co-IP and western blot. The therapeutic efficacy of Pimozide was investigated in neuroblastoma cells in vitro. RESULTS: NeuroD1 was identified as a critical regulator associated with MYCN amplification. NeuroD1 promoted the proliferation of neuroblastoma cells in vitro and in vivo. Mechanistically, NeuroD1 knockdown increased K48-linked polyubiquitination of N-Myc, leading to its proteasomal degradation. USP1 was identified as a key downstream effector of NeuroD1 and was shown to interact with N-Myc, removing K48-linked polyubiquitin chains and stabilizing the protein. Pimozide effectively suppressed USP1 expression, reduced N-Myc levels, and inhibited neuroblastoma cell proliferation. CONCLUSION: This study uncovered a novel oncogenic axis in neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, promoting N-Myc stabilization and tumor progression. Furthermore, the findings highlight the therapeutic potential of repurposing Pimozide as a promising treatment strategy for this aggressive tumor subtype.