{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Xu Y"],"funding":["Life Sciences Research Foundation","Welch Foundation (The Welch Foundation)","Terry Fox Foundation (La Fondation Terry Fox)","Cancer Prevention and Research Institute of Texas (CPRIT)","U.S. Department of Defense (DOD)","Life Sciences Research Foundation (LSRF)","Cancer Prevention and Research Institute of Texas","National Cancer Institute (NCI)","Prostate Cancer Foundation (PCF)","Terry Fox Foundation","U.S. Department of Defense","National Cancer Institute","NCI NIH HHS","Welch Foundation","Prostate Cancer Foundation","NIGMS NIH HHS"],"pagination":["1496-1521"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11285331"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(8)"],"pubmed_abstract":["Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Significance: This study reveals a bifurcated role of ZNF397, and a TET2-driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance."],"journal":["Cancer discovery"],"pubmed_title":["ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer."],"pmcid":["PMC11285331"],"funding_grant_id":["I-2005-20190330","F31CA261019-01A1","R01 CA288820","P30 CA008748","17YOUN12","R01 CA292949","W81XWH21-1-0520","W81XWH-18-1-0411","RR170050","R37 CA258730","F31 CA261019","21YOUN10","RP220473","R37CA258730","PPG19-1090","W81XWH21-1-0418","R01 GM143380","R01 CA258584","R01CA288820","R00CA218885","RP230363","R00 CA218885","T32 CA124334","R01CA258584","DDBrown awardee"],"pubmed_authors":["Raj GV","Deng S","Sjostrom M","Wang C","Hanker AB","He HH","Jiang Y","Cheng S","Feng FY","Liang H","Wang T","Chen Y","Wang Y","Mu P","Wang Z","Tang Y","Yu X","Mukherji A","Xu Q","Zhu H","Arteaga CL","Zhu G","Barnes S","Tirado CR","Li X","Wainwright G","Yang Y","Gonzalez J","Metang LA","Johnson NA","Hofstad M","Xu Y"],"additional_accession":[]},"is_claimable":false,"name":"ZNF397 Deficiency Triggers TET2-Driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.","description":"Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming that allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified zinc finger protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a ten-eleven translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR-targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Significance: This study reveals a bifurcated role of ZNF397, and a TET2-driven epigenetic mechanism regulating tumor lineage plasticity and therapy response in prostate cancer, enhances the understanding of drug resistance, and unveils a new therapeutic strategy for overcoming androgen receptor-targeted therapy resistance.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2026-06-02T23:12:41.195Z","creation":"2025-04-19T07:07:45.049Z"},"accession":"S-EPMC11285331","cross_references":{"pubmed":["38591846"],"doi":["10.1158/2159-8290.CD-23-0539"]}}