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We previously described a further role for PACT as a modulator of nuclear receptor (NR)-regulated gene expression. Here, we investigated the role of PACT in prostate cancer (PCa) using a loss-of-function approach. Depletion of PACT in multiple PCa cell lines resulted in a reduction in cell proliferation, but viability was maintained. RNA-sequencing analysis of LNCaP PCa cells\u2009\u00b1\u2009PACT revealed a depletion of biological processes involved in cell cycle, mitochondrial function, and NR-response pathways in the PACT knockout (KO) cells. In the PACT KO cells, downregulated genes included the androgen-regulated\n                    <jats:italic>KLK3<\/jats:italic>\n                    (prostate specific antigen, PSA), together with\n                    <jats:italic>H2AFJ, PSMD5, AQP3, TMEM45B<\/jats:italic>\n                    , and\n                    <jats:italic>SLC22A3,<\/jats:italic>\n                    and siRNA-mediated knockdown of these genes reduced cell growth and proliferation in LNCaP cells. Further, reducing PACT or PSA induced cell cycle arrest at G0\/G1. Additionally, the hormone-mediated upregulation and AR antagonist-driven downregulation of PSA gene expression were respectively attenuated and enhanced in PACT KO cells. Taken together, these data support a pro-proliferative role for PACT in PCa, and siRNA therapeutic targeting of PACT, or downregulated genes with PACT KO, could represent a new therapeutic approach.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-20494-9","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T09:00:31Z","timestamp":1761037231000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["PACT is requisite for prostate cancer cell proliferation"],"prefix":"10.1038","volume":"15","author":[{"given":"Dianne J.","family":"Beveridge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsty L.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikki A. 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