Abstract

Protein arginine methyltransferase 1 (PRMT1) catalyzing the formation of asymmetric dimethylarginines has been implicated in cancer development, metastasis, and prognosis. In this study, we investigated the effects of low PRMT1 levels on a non-MYCN amplified neuroblastoma SK-N-SH cell line. Stable PRMT1-knockdown (PRMT1-KD) cells showed reduced growth rates and cell cycle arrest at G2/M. They also exhibited senescent phenotypes and increased p53 expression. p21 and PAI-1, which are two p53 downstream targets critical for senescence, were significantly induced in SK-N-SH cells subjected to either PRMT1-KD or inhibitor treatment. The induction was suppressed by a p53 inhibitor and marginal in a p53-null SK-N-AS cell line, suggesting dependence on p53. In general, the DNA damage and ROS levels of the PRMT1-KD SK-N-SH cells were slightly increased. Their migration activity also increased with the induction of PAI-1. Thus, PRMT1 downregulation released the repression of cellular senescence and migration activity in SK-N-SH cells. These results might partially explain the poor prognostic outcome of low PRMT1 in a non-MYCN-amplified cohort and indicate the multifaceted complexity of PRMT1 as a biological regulator of neuroblastoma.

Highlights

  • Protein arginine methylation is a posttranslational modification implicated in signal transduction, transcriptional regulation, DNA repair and RNA processing[1,2]

  • Using tissue samples from patients with Hirschsprung disease (HSCR), we showed the distribution of human Protein arginine methyltransferase 1 (PRMT1) in neurons in the submucosal and myenteric plexuses of the enteric nervous system, which is the largest group in the peripheral nervous system (PNS)[25]

  • The analyses of the Seeger dataset with 102 patients with non-MYCN amplified neuroblastoma using the R2 platform showed unfavorable prognosis in patients with low PRMT1 expression levels (Fig. 1A)

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Summary

Introduction

Protein arginine methylation is a posttranslational modification implicated in signal transduction, transcriptional regulation, DNA repair and RNA processing[1,2]. We knocked down prmt[1] via antisense morpholino (AMO) injections in zebrafish embryos and showed defective convergence and extension during gastrulation. This knockdown affects embryonic brain development[21]. Mutant mice with prmt[1] knocked out in the central nervous system (CNS) show post-natal growth retardation with tremors, with mice dying two weeks after birth. This mouse model suggests specific roles of PRMT1 in the nervous system[22]. We aimed to study PRMT1 in neuroblastoma, a tumor derived from the neural crest cells

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