Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression
- Author(s)
- Busacca, S; Zhang, Q; Sharkey, A; Dawson, AG; Moore, DA; Waller, DA; Nakas, A; Jones, C; Cain, K; Luo, JL; Salcedo, A; Salaroglio, IC; Riganti, C; Le Quesne, J; John, T; Boutros, PC; Zhang, SD; Fennell, DA;
- Journal Title
- Scientific Reports
- Publication Type
- Research article
- 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.
- Keywords
- Biomarkers, Tumor; Cell Transformation, Neoplastic/*genetics/metabolism; Gene Deletion; *Gene Expression Regulation, Neoplastic/drug effects; Gene Silencing; Humans; Kaplan-Meier Estimate; Mesothelioma, Malignant/genetics/mortality/pathology; Prognosis; Protein-Arginine N-Methyltransferases/*genetics/metabolism; Proto-Oncogene Proteins c-jun/metabolism; Purine-Nucleoside Phosphorylase/*genetics/metabolism; Quinacrine/pharmacology; Transcription, Genetic
- Department(s)
- Medical Oncology
- PubMed ID
- 33795785
- Publisher's Version
- https://doi.org/10.1038/s41598-021-86834-7
- Open Access at Publisher's Site
https://doi.org/10.1038/s41598-021-86834-7- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-06-20 03:31:48
Last Modified: 2025-06-20 03:33:48