Universität zu Köln

Mitra, Sanhita, Muralidharan, Somsundar Veppil, Di Marco, Mirco, Juvvuna, Prasanna Kumar ORCID: 0000-0003-4296-9621, Kosalai, Subazini Thankaswamy, Reischl, Silke, Jachimowicz, Daniel, Subhash, Santhilal ORCID: 0000-0002-0077-4597, Raimondi, Ivan ORCID: 0000-0002-9522-2794, Kurian, Leo ORCID: 0000-0001-7466-5169, Huarte, Maite ORCID: 0000-0003-3753-6493, Kogner, Per, Fischer, Matthias, Johnsen, John Inge ORCID: 0000-0003-1277-812X, Mondal, Tanmoy and Kanduri, Chandrasekhar ORCID: 0000-0001-6271-9078 (2021). Subcellular Distribution of p53 by the p53-Responsive lncRNA NBAT1 Determines Chemotherapeutic Response in Neuroblastoma. Cancer Res., 81 (6). S. 1457 - 1472. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

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 wildtype 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mitra, Sanhita UNSPECIFIED UNSPECIFIED UNSPECIFIED Muralidharan, Somsundar Veppil UNSPECIFIED UNSPECIFIED UNSPECIFIED Di Marco, Mirco UNSPECIFIED UNSPECIFIED UNSPECIFIED Juvvuna, Prasanna Kumar UNSPECIFIED orcid.org/0000-0003-4296-9621 UNSPECIFIED Kosalai, Subazini Thankaswamy UNSPECIFIED UNSPECIFIED UNSPECIFIED Reischl, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED Jachimowicz, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Subhash, Santhilal UNSPECIFIED orcid.org/0000-0002-0077-4597 UNSPECIFIED Raimondi, Ivan UNSPECIFIED orcid.org/0000-0002-9522-2794 UNSPECIFIED Kurian, Leo UNSPECIFIED orcid.org/0000-0001-7466-5169 UNSPECIFIED Huarte, Maite UNSPECIFIED orcid.org/0000-0003-3753-6493 UNSPECIFIED Kogner, Per UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Johnsen, John Inge UNSPECIFIED orcid.org/0000-0003-1277-812X UNSPECIFIED Mondal, Tanmoy UNSPECIFIED UNSPECIFIED UNSPECIFIED Kanduri, Chandrasekhar UNSPECIFIED orcid.org/0000-0001-6271-9078 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-591203
DOI:	10.1158/0008-5472.CAN-19-3499
Journal or Publication Title:	Cancer Res.
Volume:	81
Number:	6
Page Range:	S. 1457 - 1472
Date:	2021
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language WILD-TYPE P53; NUCLEAR EXPORT; CYTOPLASMIC SEQUESTRATION; G(1) CHECKPOINT; GENE-MUTATIONS; LOCALIZATION; PATHWAY; CANCER; INHIBITION; CELLS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59120