TY - JOUR
T1 - JMJD6 Is a druggable oxygenase that regulates AR-V7 expression in prostate cancer
AU - SU2C/PCF International Prostate Cancer Dream Team
AU - Paschalis, Alec
AU - Welti, Jonathan
AU - Neeb, Antje J.
AU - Yuan, Wei
AU - Figueiredo, Ines
AU - Pereira, Rita
AU - Ferreira, Ana
AU - Riisnaes, Ruth
AU - Rodrigues, Daniel Nava
AU - Jiménez-Vacas, Juan M.
AU - Kim, Soojin
AU - Uo, Takuma
AU - Di Micco, Patrizio
AU - Tumber, Anthony
AU - Saiful Islam, Md
AU - Moesser, Marc A.
AU - Abboud, Martine
AU - Kawamura, Akane
AU - Gurel, Bora
AU - Christova, Rossitza
AU - Gil, Veronica S.
AU - Buroni, Lorenzo
AU - Crespo, Mateus
AU - Miranda, Susana
AU - Lambros, Maryou B.
AU - Carreira, Suzanne
AU - Tunariu, Nina
AU - Alimonti, Andrea
AU - Al-Lazikani, Bissan
AU - Schofield, Christopher J.
AU - Plymate, Stephen R.
AU - Sharp, Adam
AU - de Bono, Johann S.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/2/15
Y1 - 2021/2/15
N2 - 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 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. 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.
AB - 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 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. 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.
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U2 - 10.1158/0008-5472.CAN-20-1807
DO - 10.1158/0008-5472.CAN-20-1807
M3 - Article
C2 - 33822745
AN - SCOPUS:85102177248
SN - 0008-5472
VL - 81
SP - 1087
EP - 1100
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -