Subcellular Distribution of p53 by the p53-Responsive lncRNA NBAT1 Determines Chemotherapeutic Response in Neuroblastoma
Sanhita Mitra 1, Somsundar Veppil Muralidharan 1, Mirco Di Marco 1, Prasanna Kumar Juvvuna 1, Subazini Thankaswamy Kosalai 1, Silke Reischl 1, Daniel Jachimowicz 1, Santhilal Subhash 1, Ivan Raimondi 2, Leo Kurian 3, Maite Huarte 2, Per Kogner 4, Matthias Fischer 5, John Inge Johnsen 4, Tanmoy Mondal 6, Chandrasekhar Kanduri 7
Neuroblastoma has a low mutation rate for the p53 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 NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments.
Depletion of NBAT1 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 NBAT1-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 NBAT1-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.
CITA DEL ARTICULO Cancer Res. 2021 Mar 15;81(6):1457-1471. doi: 10.1158/0008-5472.CAN-19-3499. Epub 2020 Dec 28.