Sustained cancer-relevant alternative RNA splicing events driven by PRMT5 in high-risk neuroblastoma

Sep 21, 2026

Protein arginine methyltransferase 5 (PRMT5) is over-expressed across many cancers and contributes to oncogenic programs partly by regulating the master transcription regulator E2F1. In neuroblastoma, elevated PRMT5 and E2F1 is associated with poor prognosis high-risk disease and correlates with amplified MYCN. MYCN promotes splicing factor gene expression; with PRMT5 and E2F1, this yields a deregulated alternative RNA splicing program that blocks apoptosis. Inhibition of PRMT5 or E2F1 inactivation restores normal splicing and sensitizes cells to apoptosis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Introduction

Background on neuroblastoma risk groups and mutations

Role of E2F1 and PRMT5 in gene regulation and splicing

Link between methylation and splicing machinery

Sustained cancer-relevant alternative RNA splicing events driven by PRMT5 in high-risk neuroblastoma Laurel Tabe Bate-Eya 1, Gulsah Albayrak 1, Simon Mark Carr 1, Amit Shrestha 1, Alexander Kanapin2, Anastasia Samsonova2 and Nicholas Barrie La Thangue 1 1 Laboratory of Cancer Biology, Department of Oncology, University of Oxford, UK 2 Institute of Translational Biomedicine, Saint Petersburg State University, Russia Keywords alternative RNA splicing; apoptosis; E2F1; neuroblastoma; PRMT5; therapeutic target Correspondence N. B. La Thangue, Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK E-mail: [nick.lathangue@oncology.ox.ac.uk](nick.lathangue@oncology.ox.ac.uk) Gulsah Albayrak and Simon Mark Carr contributed equally to this article (Received 7 March 2024, revised 12 June 2024, accepted 8 July 2024, available online 17 July 2024) doi:10 . 1002/1878-0261 .13702 Protein arginine methyltransferase 5 (PRMT5) is over-expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1 . We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high-risk disease and correlates with an ampliﬁed Myelocytomatosis viral-related oncogene, neuroblastoma-derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our ﬁndings suggest that a sustained cancer-relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high-risk disease. 1. Introduction Neuroblastoma is the most common extracranial solid tumour in children and is associated with signiﬁcant morbidity and mortality [1] . The disease exhibits phenotypic heterogeneity and is broadly divided into poor prognosis high-risk and improved prognosis lower-risk disease [2], and metastatic drug-resistant disease is a major clinical challenge [3] . One of the major obstacles in developing new treatment modalities is the limited understanding of the biologically relevant cancer pathways that drive the malignant phenotype [2] . A variety of somatic mutations in oncogenic pathways have been described, for example, ampliﬁcation of the MYCN gene and mutation in the ALK and ATRX genes [4–7] MYCN gene ampliﬁcation occurs in about 25% of tumours and is a common feature of high-risk disease, with rapid disease progression and poor prognosis; abnormal MYCN expression is the strongest predictor of poor prognosis [8] . In contrast, germline Abbreviations ACIN1, apoptotic chromatin condenser inducer 1; CFLAR, CASP8 and FADD like apoptosis regulator; ChIP, chromatin immunoprecipitation; Cr, CRISPR; DEGs, differentially expressed genes; E2F1, E2 promoter binding factor 1; FACS, ﬂourescence activated cell sorting; GEO, Gene Expression Omnibus; GFP, green ﬂuorescence protein; GO, Gene Ontology; HA, Haemagglutinin; INSS, international neuroblastoma staging system; KEGG, Kyoto Encyclopedia of Genes and Genomes; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide; MYCN, myelocytomatosis viral-related oncogene, neuroblastoma derived; NB, neuroblastoma; ORF, open reading frame; OS, overall survival; pRb, retinoblastoma protein; PRMT5, protein arginine methyltransferase 5; PSI, per cent spliced in; rMATS, replicate multivariate analysis of transcript splicing; TARGET, therapeutically applicable research to generate effective treatments; TCGA, The Cancer Genome Atlas; Vst, variance stabilising transformation; WT, wild type. Molecular Oncology 19

FAQs

What is the role of PRMT5 and E2F1 in high-risk neuroblastoma?

The article reports that PRMT5 and E2F1 are elevated in poor prognosis high-risk neuroblastoma and correlate with amplified MYCN, linking them to an oncogenic regulatory program.

How does MYCN influence alternative RNA splicing in neuroblastoma?

MYCN drives expression of splicing factor genes. Together with PRMT5 and E2F1, this produces a deregulated alternative RNA splicing program.

How do inhibiting PRMT5 or inactivating E2F1 affect apoptosis?

PRMT5 inhibition or E2F1 inactivation restores normal splicing and sensitizes neuroblastoma cells to apoptosis, countering the apoptosis-impeding splicing program.

Sep 21, 2026

Uploaded by Valentina