JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
Paschalis A., Welti J., Neeb AJ., Yuan W., Figueiredo I., Pereira R., Ferreira A., Riisnaes R., Rodrigues DN., Jiménez-Vacas JM., Kim S., Uo T., Micco PD., Tumber A., Islam MS., Moesser MA., Abboud M., Kawamura A., Gurel B., Christova R., Gil VS., Buroni L., Crespo M., Miranda S., Lambros MB., Carreira S., Tunariu N., Alimonti A., Al-Lazikani B., Schofield CJ., Plymate SR., Sharp A., de Bono JS., , SU2C/PCF International Prostate Cancer Dream Team None.
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 = 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. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.