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In this study, we reveal the clinical significance and mechanistic role of the off-pore NUP, soluble POM121 (sPOM121), as a crucial transcriptional regulator that enhances the aggressiveness of metastatic prostate cancer. Using orthogonal methodologies in human samples, sPOM121 was identified as the predominantly expressed nucleoplasmic NUP in prostate cancer. Unbiased proteomic and epigenomic studies demonstrate that sPOM121, through its C-terminus, interacts with the chromatin remodeler SMARCA5 at gene promoter sites and localizes at nuclear condensates, reprogramming gene expression. Indeed, sPOM121 regulates a distinct oncogenic gene network, including \u03b2-catenin, leading to prostate cancer progression and immune evasion. Importantly, targeting the sPOM121\/\u03b2-catenin axis in patient-derived preclinical and syngeneic mouse models halts prostate cancer aggressiveness and enhances antitumor immunity. Taken together, these findings reveal previously unknown actionable reprogramming functions of off-pore NUPs in solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study uncovers how oncogenic signaling programs are transcriptionally heightened by the NUP sPOM121 in metastatic prostate cancer. Localization of sPOM121 at active transcriptional nuclear condensates propels disease progression and immune evasion, offering novel anticancer therapeutic opportunities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0629","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T12:19:41Z","timestamp":1753445981000},"page":"2374-2396","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Off-pore Nucleoporin sPOM121 Transcriptionally Propels \u03b2-Catenin\u2013driven Tumor Progression and Immune Escape in Prostate Cancer"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9638-1615","authenticated-orcid":false,"given":"Perumalraja","family":"Kirthika","sequence":"first","affiliation":[{"name":"1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota."},{"name":"2Department of Urology, Mayo Clinic, Rochester, Minnesota."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8492-5550","authenticated-orcid":false,"given":"Vijayakumar","family":"Jawalagatti","sequence":"additional","affiliation":[{"name":"1Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota."},{"name":"2Department of Urology, Mayo Clinic, Rochester, Minnesota."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9119-2498","authenticated-orcid":false,"given":"Peiyao","family":"Li","sequence":"additional","affiliation":[{"name":"3Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, Pennsylvania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1801-2611","authenticated-orcid":false,"given":"Michael","family":"Xu","sequence":"additional","affiliation":[{"name":"3Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, Pennsylvania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6648-215X","authenticated-orcid":false,"given":"Marc","family":"Carceles-Cordon","sequence":"additional","affiliation":[{"name":"2Department of Urology, Mayo Clinic, Rochester, Minnesota."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7455-1559","authenticated-orcid":false,"given":"Adam","family":"Ertel","sequence":"additional","affiliation":[{"name":"3Sidney Kimmel Cancer Center Thomas Jefferson University, Philadelphia, Pennsylvania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6557-9186","authenticated-orcid":false,"given":"S. Aidan","family":"Quinn","sequence":"additional","affiliation":[{"name":"4Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts."},{"name":"5Broad Institute of MIT and Harvard, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6165-5797","authenticated-orcid":false,"given":"Daniel P.","family":"Petrylak","sequence":"additional","affiliation":[{"name":"6Department of Medical Oncology, Yale Cancer Center, Yale University, New Haven, Connecticut."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-0239","authenticated-orcid":false,"given":"Jacob J.","family":"Orme","sequence":"additional","affiliation":[{"name":"7Department of Medical Oncology, Mayo Clinic, Rochester, 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