{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T01:00:19Z","timestamp":1755219619355,"version":"3.43.0"},"reference-count":45,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013415","name":"Purdue University Center for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013415","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer responsible for an estimated 20%\u201330% of castration\u2010resistant prostate cancer (CRPC) deaths. While NEPC can arise spontaneously, the majority of these cases emerge as treatment\u2010induced NEPC (tNEPC). Our clinical and computational analyses identified increased expression of protein methyltransferase 5 (PRMT5) and its cofactor methylosome protein 50 (MEP50) in tNEPC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here we generated an in vitro cell culture and mouse model of prostate cancer to recapitulate tNEPC induced upon treatment with the androgen receptor (AR) inhibitor, enzalutamide. The role of PRMT5 and its cofactor MEP50 were determined by overexpression. Depletion of these genes and pharmacological inhibition of PRMT5 were followed by analysis of cell viability, neurite growth, and effects on neuroendocrine\u2010related gene transcription using immunofluorescence, immunohistochemistry, and Western blot. PRMT5 and MEP50 protein expression levels were comprehensively analyzed for clinical correlation in NEPC patient prostate tissue samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Elevated PRMT5 and MEP50 correlated with increased recurrence in prostate cancer patients receiving androgen deprivation therapy. Depletion of PRMT5 and MEP50 prevented neuroendocrine differentiation (NED)\u2010induced by enzalutamide both in vitro and in a xenograft mouse model. Conversely, overexpression of PRMT5 and MEP50 was sufficient to induce NED in prostate cancer cells. Evaluation of a genetically engineered mouse model, in which PRMT5 and MEP50 were overexpressed in the prostate, similarly indicated NEPC development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data suggest that PRMT5:MEP50 are regulators of tNEPC. PRMT5\/MEP50 expression could serve as a predictive biomarker and therapeutic target for aggressive forms of prostate cancer.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.70006","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T05:39:29Z","timestamp":1752817169000},"page":"1196-1207","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PRMT5:MEP50 Are Mediators of Treatment\u2010Induced Neuroendocrine Differentiation in Prostate Cancer"],"prefix":"10.1002","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9556-8920","authenticated-orcid":false,"given":"Hye Seung","family":"Nam","sequence":"first","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew Michael","family":"Asberry","sequence":"additional","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuehong","family":"Deng","sequence":"additional","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis Indiana USA"},{"name":"Indiana University Simon Comprehensive Cancer Center Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaoti","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University School of Medicine Duke University Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang\u2010Deng","family":"Hu","sequence":"additional","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette Indiana USA"},{"name":"Purdue Institute for Cancer Research Purdue University West Lafayette Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis Indiana USA"},{"name":"Indiana University Simon Comprehensive Cancer Center Indiana University School of Medicine Indianapolis Indiana USA"},{"name":"Center for Computational Biology and Bioinformatics Indiana University School of Medicine Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael K.","family":"Wendt","sequence":"additional","affiliation":[{"name":"Borch Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette Indiana USA"},{"name":"Purdue Institute for Cancer Research Purdue University West Lafayette Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"volume-title":"American Cancer Society: Cancer Facts & Figures 2003","year":"2003","key":"e_1_2_9_2_1"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-0902"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.22.4.232?sid=nlm:pubmed"},{"issue":"2","key":"e_1_2_9_5_1","first-page":"52","article-title":"Effective Testosterone Suppression for Prostate Cancer: Is There a Best Castration Therapy?","volume":"11","author":"Gomella L. 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