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

Sara Busacca, Qi Zhang, Annabel Sharkey, Alan G Dawson, David A Moore, David A Waller, Apostolos Nakas, Carolyn Jones, Kelvin Cain, Jin-Li Luo, Adriana Salcedo, Iris Chiara Salaroglio, Chiara Riganti, John Le Quesne, Tom John, Paul C Boutros, Shu-Dong Zhang, Dean A Fennell

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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.
Original languageEnglish
Article number7434
Number of pages10
JournalScientific Reports
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Apr 2021

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