Subcellular Distribution of p53 by the p53-Responsive lncRNA <i>NBAT1</i> Determines Chemotherapeutic Response in Neuroblastoma

Abstract

Neuroblastoma has a low mutation rate for the <i>p53</i> gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor <i>NBAT1</i> is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of <i>NBAT1</i> provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of <i>NBAT1</i> altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized <i>NBAT1</i>-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an <i>NBAT1</i>-dependent CRM1/MDM2-based potential combination therapy for patients with high-risk neuroblastoma. SIGNIFICANCE: This study shows how a p53-responsive lncRNA mediates chemotherapeutic response by modulating nuclear p53 pathways and identifies a potential treatment strategy for patients with high-risk neuroblastoma.