GSE130520
AVEN is an indirectly druggable mediator of neuroblastoma cell tumorigenicity and chemotherapy resistance [RNA-seq]
Approximately half of children diagnosed with neuroblastoma have aggressive high-risk disease, against which current multimodal therapy has little success. New targets for therapeutic intervention are urgently needed. In a systems approach, we combined time-resolved mRNA-Seq with miRNA profiling in a model of neuroblastoma differentiation treated with or without the clinically approved histone deacetylase inhibitor, panobinostat. Treatment most strongly regulated miR-630, which strongly downregulated AVEN, an inhibitor of apoptosis. Here we characterized AVEN for the first time in neuroblastoma pathogenesis, disclosed its epigenetic regulation and discovered correlations between AVEN expression and resistance to chemotherapy. High-level AVEN expression in 649 primary neuroblastomas negatively correlated with patient survival. Stably enforcing AVEN expression in BE(2)-C cells markedly promoted growth as subcutaneous xenografts in mice, while CRISP/Cas9-mediated AVEN knockout in BE(2)-C cells substantially reduced xenograft growth and enhances the efficacy of systemic doxorubicin treatment. Cell-based assays, flow cytometric cell cycle analyses and SILAC experiments demonstrate that AVEN is required for neuroblastoma proliferation. Overall design: Panobinostat induced gene expression in human neuroblastoma BE(2)-C cells, treated with 5 nM, 10 nM or 15 nM for 6 h and 12 h.