title: Protein arginine methyltransferase 1 is a novel regulator of MYCN in neuroblastoma.
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.
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Allison
authors: A
authors: Eberhardt
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Jeanne N
authors: JN
authors: Hansen
authors: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors: Jan
authors: J
authors: Koster
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Louis T
authors: LT
authors: Lotta
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Simeng
authors: S
authors: Wang
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Emmett
authors: E
authors: Livingstone
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
authors: Kun
authors: K
authors: Qian
authors: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors: Linda J
authors: LJ
authors: Valentijn
authors: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
authors: Yujun George
authors: YG
authors: Zheng
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Nina F
authors: NF
authors: Schor
authors: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA.
authors: Xingguo
authors: X
authors: Li
mesh_terms: D001120:Arginine / Q000737:chemistry; D001932:Brain Neoplasms / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D013912:Threonine; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: MYCN; PRMT1; arginine methylation; neuroblastoma; protein stability