{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T17:00:08Z","timestamp":1775581208115,"version":"3.50.1"},"reference-count":120,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R21CA226654-01A1"],"award-info":[{"award-number":["R21CA226654-01A1"]}]},{"name":"NIH","award":["R21CA226654-01A1S1"],"award-info":[{"award-number":["R21CA226654-01A1S1"]}]},{"name":"NIH","award":["R21CA280647"],"award-info":[{"award-number":["R21CA280647"]}]},{"name":"NIH","award":["R25GM060507"],"award-info":[{"award-number":["R25GM060507"]}]},{"name":"NIH","award":["2230289"],"award-info":[{"award-number":["2230289"]}]},{"name":"Loma Linda University","award":["R21CA226654-01A1"],"award-info":[{"award-number":["R21CA226654-01A1"]}]},{"name":"Loma Linda University","award":["R21CA226654-01A1S1"],"award-info":[{"award-number":["R21CA226654-01A1S1"]}]},{"name":"Loma Linda University","award":["R21CA280647"],"award-info":[{"award-number":["R21CA280647"]}]},{"name":"Loma Linda University","award":["R25GM060507"],"award-info":[{"award-number":["R25GM060507"]}]},{"name":"Loma Linda University","award":["2230289"],"award-info":[{"award-number":["2230289"]}]},{"name":"Loma Linda University School of Medicine Center for Health Disparities and Molecular Medicine","award":["R21CA226654-01A1"],"award-info":[{"award-number":["R21CA226654-01A1"]}]},{"name":"Loma Linda University School of Medicine Center for Health Disparities and Molecular Medicine","award":["R21CA226654-01A1S1"],"award-info":[{"award-number":["R21CA226654-01A1S1"]}]},{"name":"Loma Linda University School of Medicine Center for Health Disparities and Molecular Medicine","award":["R21CA280647"],"award-info":[{"award-number":["R21CA280647"]}]},{"name":"Loma Linda University School of Medicine Center for Health Disparities and Molecular Medicine","award":["R25GM060507"],"award-info":[{"award-number":["R25GM060507"]}]},{"name":"Loma Linda University School of Medicine Center for Health Disparities and Molecular Medicine","award":["2230289"],"award-info":[{"award-number":["2230289"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>An emerging challenge in prostate cancer (PCa) treatment is the development of drug cross-resistance, wherein resistance to enzalutamide (ENZ), an androgen receptor signaling inhibitor (ARSI), also confers resistance to subsequent ARSI and docetaxel (DTX) treatments. The mechanisms underlying this drug cross-resistance remain unclear. Through RNA sequencing, we identified 93 overlapping differentially expressed genes (DEGs) in ENZ- and DTX-resistant PCa cells. Among the DEGs, HSPB1, which encodes heat shock protein 27 (HSP27), emerged as a key gene of interest. HSP27 is a known target of lens epithelium-derived growth factor p75 (LEDGF\/p75), a transcription coactivator regulated by glucocorticoid receptor (GR). Both GR and LEDGF\/p75 are overexpressed in advanced PCa and promote drug resistance. HSP27 was overexpressed in ENZ and DTX cross-resistant PCa cell lines and its expression was decreased upon GR or LEDGF\/p75 silencing. ChIP sequencing confirmed GR binding at the HSPB1 promoter. Pharmacological targeting of HSP27 in drug-resistant cells reduced proliferation, clonogenicity, and tumorsphere formation, and restored sensitivity to ENZ and DTX. Notably, high transcript expression of a GR-LEDGF\/p75-HSP27 gene panel correlated with worse overall survival in PCa patients (n = 4259). These findings identified this axis as a driver of PCa drug cross-resistance and promising therapeutic target for overcoming treatment failure.<\/jats:p>","DOI":"10.3390\/cells14191566","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T09:41:02Z","timestamp":1760002862000},"page":"1566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The GR-LEDGF\/p75-HSP27 Axis Contributes to Cross-Resistance Between Enzalutamide and Docetaxel in Prostate Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Pedro T.","family":"Ochoa","sequence":"first","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evelyn S.","family":"Sanchez-Hernandez","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfonso M.","family":"Duran","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"},{"name":"Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"},{"name":"Urology Department, Loma Linda University Medical Center, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Philip","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tise","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5864-4704","authenticated-orcid":false,"given":"Julia J.","family":"Unternaehrer","sequence":"additional","affiliation":[{"name":"Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Dutil","sequence":"additional","affiliation":[{"name":"University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00921, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhaskar","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14215, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rituparna","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmine","family":"Baca","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8250-2183","authenticated-orcid":false,"given":"David","family":"de Semir","sequence":"additional","affiliation":[{"name":"Caris Life Sciences, Phoenix, AZ 85040, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Center for Genomics, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isaac","family":"Kremsky","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Division of Biomedical Engineering Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7320-4333","authenticated-orcid":false,"given":"Carlos 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