Abstract
Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 years and have now entered oncology clinical trials, including for brain tumours. This review collates recent advances in the understanding of the role of PRMTs and arginine methylation in brain tumours. We provide an up-to-date literature review on the mechanisms for PRMT regulation. These include endogenous modulators such as alternative splicing, miRNA, post-translational modifications and PRMT–protein interactions, and synthetic inhibitors. We discuss the relevance of PRMTs in brain tumours with a particular focus on PRMT1, -2, -5 and -8. Finally, we include a future perspective where we discuss possible routes for further research on arginine methylation and on the use of PRMT inhibitors in the context of brain tumours.
Highlights
Gliomas are the commonest malignancy of the central nervous system with the most devastating form of glioma being grade IV astrocytoma, known as glioblastoma (GBM) (Ostrom et al 2018)
protein arginine methyltransferases (PRMTs) present a novel target for GBM treatment due to their ability to augment a vast variety of cellular processes related to cell growth, including growth factor signalling, DNA damage repair and proliferation, coupled with their increased expression in GBM tumour cells and tissues
Tools to investigate arginine methylation (ArgMe) have been developed over the past decade and include PRMT inhibitors
Summary
Gliomas are the commonest malignancy of the central nervous system with the most devastating form of glioma being grade IV astrocytoma, known as glioblastoma (GBM) (Ostrom et al 2018). In contrast to most other PRMTs, PRMT8 seems to have a reduced transcript expression in GBM patient tissue when compared with normal tissue, suggesting it may be down regulated during tumour development (Simandi et al 2015) This decrease in expression was accompanied by a significant increase in the expression of C-X-C chemokine receptor type 4 (Cxcr4) and epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (Efemp). Knock-down of a previously unknown PRMT8 transcript variant, named PRMT8 variant 2, was shown to reduce proliferation of the GBM cell line U-87MG (Hernandez and Dominko 2016) This variant of PRMT8 shows nuclear localisation, due to the loss of the myristoylation motif in the N-terminal domain, and most likely acts through epigenetic regulation of gene expression (Hernandez et al 2017). Upon nuclear localisation through the loss of its myristoylation motif, PRMT8 appears to have a switch in molecular targets, which confers a tumorigenic phenotype, most likely similar to PRMT1
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