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Thus, targeting the AR N\u2010terminal domain (NTD) could overcome such resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Luciferase reporter assays after transient transfection of various DNA constructs were used to assess effects of E1A proteins on AR\u2010mediated transcription. Immunofluorescence microscopy and subcellular fractionation were applied to assess intracellular protein localization. Immunoprecipitation and mammalian two\u2010hybrid assays were used to detect protein\u2010protein interactions. qRT\u2010PCR was employed to determine RNA levels. Western blotting was used to detect protein expression in cells. Effects of adenoviruses on prostate cancer cell survival were evaluated with CellTiter\u2010Glo assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Adenovirus 12 E1A (E1A12) binds specifically to the AR. Interestingly, the full\u2010length E1A12 (266 aa) preferentially binds to full\u2010length AR, while the small E1A12 variant (235 aa) interacts more strongly with AR\u2010V7. E1A12 promotes AR nuclear translocation, likely through mediating intramolecular AR NTD\u2010LBD interactions. In the nucleus, AR and E1A12 co\u2010expression in AR\u2010null PCa cells results in E1A12 redistribution from nuclear foci containing CBX4 (also known as Pc2), suggesting a preferential AR\u2010E1A12 interaction over other E1A12 interactors. E1A12 represses AR\u2010mediated transcription in reporter gene assays and endogenous AR target genes such as ATAD2 and MYC in AR\u2010expressing PCa cells. AR\u2010expressing PCa cells are more sensitive to death induced by a recombinant adenovirus expressing E1A12 (Ad\u2010E1A12) than AR\u2010deficient PCa cells, which could be attributed to the increased viral replication promoted by androgen stimulation. Targeting the AR by E1A12 promotes apoptosis in PCa cells that express the full\u2010length AR or C\u2010terminally truncated AR variants. Importantly, inhibition of mTOR signaling that blocks the expression of anti\u2010apoptotic proteins markedly augments Ad\u2010E1A12\u2010induced apoptosis of AR\u2010expressing cells. Mechanistically, Ad\u2010E1A12 infection triggers apoptotic response while activating the PI3K\u2010AKT\u2010mTOR signaling axis; thus, mTOR inhibition enhances apoptosis in AR\u2010expressing PCa cells infected by Ad\u2010E1A12.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Ad12 E1A inhibits AR\u2010mediated transcription and suppresses PCa cell survival, suggesting that targeting the AR by E1A12 might have therapeutic potential for treating advanced PCa with heightened AR signaling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.23689","type":"journal-article","created":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T04:40:34Z","timestamp":1531716034000},"page":"1140-1156","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival"],"prefix":"10.1002","volume":"78","author":[{"given":"Dawei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology Qilu Hospital of Shandong University Jinan P. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa Y.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology UF Health Cancer Center and UF Genetics Institute University of Florida College of Medicine Gainesville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Co","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology UF Health Cancer Center and UF Genetics Institute University of Florida College of Medicine Gainesville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe C.","family":"Underill","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology UF Health Cancer Center and UF Genetics Institute University of Florida College of Medicine Gainesville Florida"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe 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