GATA3-driven CDC20 activation facilitates tumor growth and metastasis through suppressing Bax/Bcl-2 ratio and boosting EMT process in neuroblastoma.

Neuroblastoma (NB) is a heterogeneous pediatric malignancy in which many high-risk tumors lack MYCN amplification, necessitating the identification of alternative molecular drivers. Here, integrative transcriptomic analyses of MYCN-nonamplified NB cohorts identified cell division cycle 20 (CDC20) as a candidate associated with high-risk disease and metastasis. CDC20 expression was elevated in aggressive NB across subtypes and correlated with adverse clinical outcomes, with particularly informative prognostic value in MYCN-nonamplified patients. Functional studies established CDC20 as a potent oncogene that promotes proliferation, migration, apoptosis resistance, and tumor progression in NB models, regardless of MYCN status. Pharmacological inhibition of CDC20 further supported CDC20 as a potential therapeutic vulnerability in NB. Mechanistically, we found that the transcription factor GATA3 directly bound a specific motif within the CDC20 promoter, as validated by ChIP-qPCR and site-directed point mutagenesis, and transcriptionally activated its expression. Reciprocal genetic epistasis experiments further showed that CDC20 depletion attenuated GATA3-driven oncogenic phenotypes, whereas restoring CDC20 rescued the impaired growth, migration, and survival caused by GATA3 depletion. At the downstream level, CDC20 facilitates NB progression via dual mechanisms: suppressing the pro-apoptotic Bax/Bcl-2 ratio and inducing an epithelial-mesenchymal transition-like phenotype conducive to metastasis. Collectively, our study delineates a previously uncharacterized GATA3-CDC20 regulatory axis that promotes NB progression and identifies CDC20 as a potential therapeutic vulnerability across NB subtypes, while highlighting its particular potential for risk stratification in MYCN-nonamplified disease.