%0 Journal Article %A Paschalis, Alec %A Welti, Jonathan %A Neeb, Antje J %A Yuan, Wei %A Figueiredo, Ines %A Pereira, Rita %A Ferreira, Ana %A Riisnaes, Ruth %A Rodrigues, Daniel Nava %A Jimenez-Vacas, Juan M %A Kim, Soojin %A Uo, Takuma %A Micco, Patrizio Di %A Tumber, Anthony %A Islam, Md Saiful %A Moesser, Marc A %A Abboud, Martine %A Kawamura, Akane %A Gurel, Bora %A Christova, Rossitza %A Gil, Veronica S %A Buroni, Lorenzo %A Crespo, Mateus %A Miranda, Susana %A Lambros, Maryou B %A Carreira, Suzanne %A Tunariu, Nina %A Alimonti, Andrea %A Al-Lazikani, Bissan %A Schofield, Christopher J %A Plymate, Stephen R %A Sharp, Adam %A de Bono, Johann S %T JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. %D 2020 %U http://hdl.handle.net/10668/17533 %X Endocrine 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 ΒΌ 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. %K Alternative splicing %K Antineoplastic agents %K Cell line, tumor %K Cohort studies %K Enzyme inhibitors %K Gene expression regulation, neoplastic %~