Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression
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 (...
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Nature Portfolio
2021
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oai:doaj.org-article:6d5abf6e1ac14ad9997c92268bf3d48f2021-12-02T18:17:41ZTranscriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression10.1038/s41598-021-86834-72045-2322https://doaj.org/article/6d5abf6e1ac14ad9997c92268bf3d48f2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-86834-7https://doaj.org/toc/2045-2322Abstract 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.Sara BusaccaQi ZhangAnnabel SharkeyAlan G. DawsonDavid A. MooreDavid A. WallerApostolos NakasCarolyn JonesKelvin CainJin-li LuoAdriana SalcedoIris Chiara SalaroglioChiara RigantiJohn Le QuesneTom JohnPaul C. BoutrosShu-Dong ZhangDean A. FennellNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021) |
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Medicine R Science Q 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 Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Sara Busacca |
| title |
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression |
| title_short |
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression |
| title_full |
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression |
| title_fullStr |
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression |
| title_full_unstemmed |
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression |
| title_sort |
transcriptional perturbation of protein arginine methyltransferase-5 exhibits mtap-selective oncosuppression |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/6d5abf6e1ac14ad9997c92268bf3d48f |
| work_keys_str_mv |
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1718378280821719040 |