{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:26:16Z","timestamp":1792790776408,"version":"4.5.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The British Lung Foundation","award":["MESOUK15-11"],"award-info":[{"award-number":["MESOUK15-11"]}],"id":[{"id":"https:\/\/ror.org\/05qnwyb92","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The British Lung Foundation","award":["MESOUK15-11"],"award-info":[{"award-number":["MESOUK15-11"]}],"id":[{"id":"https:\/\/ror.org\/05qnwyb92","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1038\/s41598-021-86834-7","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T06:03:08Z","timestamp":1617256988000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression"],"prefix":"10.1038","volume":"11","author":[{"given":"Sara","family":"Busacca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Sharkey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan G.","family":"Dawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Waller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apostolos","family":"Nakas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin","family":"Cain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-li","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Salcedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris Chiara","family":"Salaroglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Riganti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Le Quesne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul C.","family":"Boutros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Dong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean A.","family":"Fennell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,1]]},"reference":[{"key":"86834_CR1","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/0165-4608(95)00157-3","volume":"86","author":"H Zhang","year":"1996","unstructured":"Zhang, H., Chen, Z. H. & Savarese, T. M. Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-alpha1, interferon-beta1, and other 9p21 markers in human malignant cell lines. Cancer Genet. Cytogenet. 86, 22\u201328. https:\/\/doi.org\/10.1016\/0165-4608(95)00157-3 (1996).","journal-title":"Cancer Genet. Cytogenet."},{"key":"86834_CR2","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1126\/science.aad5214","volume":"351","author":"GV Kryukov","year":"2016","unstructured":"Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214\u20131218. https:\/\/doi.org\/10.1126\/science.aad5214 (2016).","journal-title":"Science"},{"key":"86834_CR3","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1002\/iub.278","volume":"61","author":"E Albers","year":"2009","unstructured":"Albers, E. Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5\u2019-methylthioadenosine. IUBMB Life 61, 1132\u20131142. https:\/\/doi.org\/10.1002\/iub.278 (2009).","journal-title":"IUBMB Life"},{"key":"86834_CR4","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/j.celrep.2016.03.043","volume":"15","author":"K Marjon","year":"2016","unstructured":"Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A\/PRMT5\/RIOK1 axis. Cell Rep. 15, 574\u2013587. https:\/\/doi.org\/10.1016\/j.celrep.2016.03.043 (2016).","journal-title":"Cell Rep."},{"key":"86834_CR5","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1126\/science.aad5944","volume":"351","author":"KJ Mavrakis","year":"2016","unstructured":"Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP\/CDKN2A-deleted cancers leads to dependence on PRMT5. 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PLoS ONE 6, e16382. https:\/\/doi.org\/10.1371\/journal.pone.0016382 (2011).","journal-title":"PLoS ONE"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86834-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86834-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86834-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T01:09:10Z","timestamp":1670029750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-86834-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,1]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["86834"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-86834-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,1]]},"assertion":[{"value":"21 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"DAF has received research funding or in-kind support from Bayer, Boehringer Ingelheim, BMS, Clovis Oncology, Eli Lilly, MSD, Roche, Atlas Biodmed; Advisor to Atara, Aldeyra, Bayer, Inventiva; speaker fees from Astra Zeneca, Bristol Myers Squibb, Boehringer Ingelheim, BMS, MSD, Roche. DM reports speaker\u2019s fees from AstraZeneca. All other authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7434"}}