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

Allison Eberhardt,Yujun George Zheng,Jan Koster,Xingguo Li,Jeanne N Hansen,Emmett Livingstone,Simeng Wang,Louis T Lotta,Nina F Schor,Linda J Valentijn,Kun Qian

doi:10.18632/oncotarget.11556

Allison Eberhardt, Yujun George Zheng + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.11556

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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.

Highlights

Amplification of MYCN oncogene has proven to be a major negative prognostic biomarker for neuroblastoma, an aggressive childhood cancer with overall survival of less than 50% for high-risk disease [1]
We have previously identified protein arginine methyltransferase 1 (PRMT1) within the functional MYCN-157 signature that characterizes neuroblastoma tumors with MYCN amplification, as well as tumors with high MYCN protein levels without MYCN amplification
In line with its relationship to MYCN, we demonstrated that high expression of PRMT1 is associated with a poor prognosis in a series of 88 primary neuroblastoma tumors [3]

Summary

INTRODUCTION

Amplification of MYCN oncogene has proven to be a major negative prognostic biomarker for neuroblastoma, an aggressive childhood cancer with overall survival of less than 50% for high-risk disease [1]. A plethora of data has been generated regarding the oncogenic functions of MYCN in neuroblastoma [2]. Translation of this wealth of information into novel, effective, molecularly-targeted therapies is urgently needed. The gene protein arginine methyltransferase 1 (PRMT1) was identified as a MYCN direct target gene and high levels of PRMT1 mRNA correlated with poor prognosis in a series of 88 primary neuroblastoma tumors. Protein arginine methylation has been implicated in signal transduction, gene transcription, DNA repair and mRNA splicing, among other functions and aberrant expression of PRMT1 has been found in various types of cancer [4]. Our results highlight the potential of PRMT1 as a drug target for neuroblastoma and other cancers driven by the MYCN oncoprotein

Results and discussion

Materials and methods

Conflicts of Interest