Paschalis, AlecWelti, JonathanNeeb, Antje JYuan, WeiFigueiredo, InesPereira, RitaFerreira, AnaRiisnaes, RuthRodrigues, Daniel NavaJimenez-Vacas, Juan MKim, SoojinUo, TakumaMicco, Patrizio DiTumber, AnthonyIslam, Md SaifulMoesser, Marc AAbboud, MartineKawamura, AkaneGurel, BoraChristova, RossitzaGil, Veronica SBuroni, LorenzoCrespo, MateusMiranda, SusanaLambros, Maryou BCarreira, SuzanneTunariu, NinaAlimonti, AndreaAl-Lazikani, BissanSchofield, Christopher JPlymate, Stephen RSharp, Adamde Bono, Johann S2023-02-092023-02-092020-12-02Paschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, et al. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. Cancer Res. 2021 Feb 15;81(4):1087-1100http://hdl.handle.net/10668/17533Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P< 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P ¼ 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease.enAlternative splicingAntineoplastic agentsCell line, tumorCohort studiesEnzyme inhibitorsGene expression regulation, neoplasticHumansJumonji domain-containing histone demethylasesMaleMolecular targeted therapyOxygenasesPrognosisProstatic neoplasms, castration-resistantProtein isoformsReceptors, androgenRetrospective studiesresearch article33822745open accessHistona demetilasas con dominio de JumonjiIsoformas de proteínasNeoplasias de la próstata resistentes a la castraciónOxigenasasPronósticoReceptores androgénicosTerapia molecular dirigida10.1158/0008-5472.CAN-20-18071538-7445PMC8025710https://aacrjournals.org/cancerres/article-pdf/81/4/1087/3165369/1087.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025710/pdf