Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression

Busacca, S. et al. (2021) Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression. Scientific Reports, 11, 7434. (doi: 10.1038/s41598-021-86834-7) (PMID:33795785) (PMCID:PMC8016828)

Abstract

We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.

• Item Type: Articles
• Additional Information: Funding: This work has been funded by The British Lung Foundation (MESOUK15-11).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Le Quesne, Professor John

Creator Roles

Le Quesne, J.: Data curation, Writing – review and editing

• Authors: Busacca, S., Zhang, Q., Sharkey, A., Dawson, A. G., Moore, D. A., Waller, D. A., Nakas, A., Jones, C., Cain, K., Luo, J.-l., Salcedo, A., Salaroglio, I. C., Riganti, C., Le Quesne, J., John, T., Boutros, P. C., Zhang, S.-D., and Fennell, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © The Author(s) 2021
• First Published: First published in Scientific Reports 11:7434
• Publisher Policy: Reproduced under a Creative Commons licence