RESUMEN

Given the paucity of druggable mutations in high-risk neuroblastoma (NB), we undertook chromatin-focused small interfering RNA and chemical screens to uncover epigenetic regulators critical for the differentiation block in high-risk NB. High-content Opera imaging identified 53 genes whose loss of expression led to a decrease in NB cell proliferation and 16 also induced differentiation. From these, the secondary chemical screen identified SETD8, the H4K20me1 methyltransferase, as a druggable NB target. Functional studies revealed that SETD8 ablation rescued the pro-apoptotic and cell-cycle arrest functions of p53 by decreasing p53K382me1, leading to activation of the p53 canonical pathway. In pre-clinical xenograft NB models, genetic or pharmacological (UNC0379) SETD8 inhibition conferred a significant survival advantage, providing evidence for SETD8 as a therapeutic target in NB.

Asunto(s)

Epigénesis Genética , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Neuroblastoma/tratamiento farmacológico , ARN Interferente Pequeño/genética , Proteína p53 Supresora de Tumor/fisiología , Diferenciación Celular , Proliferación Celular , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/fisiología , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Quinazolinas/farmacología , Proteína p53 Supresora de Tumor/análisis