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Oncotarget. 2016 Sep 27;7(39):63629-63639. doi: 10.18632/oncotarget.11556.

Protein arginine methyltransferase 1 is a novel regulator of MYCN in neuroblastoma.

Author information

1
Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
2
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
3
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.

Abstract

Amplification or overexpression of MYCN is associated with poor prognosis of human neuroblastoma. We have recently defined a MYCN-dependent transcriptional signature, including protein arginine methyltransferase 1 (PRMT1), which identifies a subgroup of patients with high-risk disease. Here we provide several lines of evidence demonstrating PRMT1 as a novel regulator of MYCN and implicating PRMT1 as a potential therapeutic target in neuroblastoma pathogenesis. First, we observed a strong correlation between MYCN and PRMT1 protein levels in primary neuroblastoma tumors. Second, MYCN physically associates with PRMT1 by direct protein-protein interaction. Third, depletion of PRMT1 through siRNA knockdown reduced neuroblastoma cell viability and MYCN expression. Fourth, we showed that PRMT1 regulates MYCN stability and identified MYCN as a novel substrate of PRMT1. Finally, we demonstrated that mutation of putatively methylated arginine R65 to alanine decreased MYCN stability by altering phosphorylation at residues serine 62 and threonine 58. These results provide mechanistic insights into the modulation of MYCN oncoprotein by PRMT1, and suggest that targeting PRMT1 may have a therapeutic impact on MYCN-driven oncogenesis.

KEYWORDS:

MYCN; PRMT1; arginine methylation; neuroblastoma; protein stability

PMID:
27571165
PMCID:
PMC5325390
DOI:
10.18632/oncotarget.11556
[Indexed for MEDLINE]
Free PMC Article

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