Journal
CANCER RESEARCH
Volume 81, Issue 4, Pages 1087-1100Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-1807
Keywords
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Categories
Funding
- Stand Up To Cancer-Prostate Cancer Dream Team Translational Research Grant [SU2C-AACR-DT0712]
- Cancer Research UK
- Prostate Cancer UK Research Innovation Award [RIA17-ST2-014]
- European Research Council Consolidator Grant [683136]
- Swiss Cancer League [4267]
- Swiss National Science Foundation [176045]
- Prostate Cancer Foundation [19CHAL08]
- Italian Association for Cancer Research Investigator Grant [22030]
- CRUK [C8717/A18245]
- Wellcome Trust [106244/Z/14/Z]
- DOD [W81XWH-17-0323, W81XWH-20-0146, W81XWH-17-0414]
- Veterans Affairs Research Service Merit Award
- Senior Clinician Scientist Research Award
- Academy of Medical Sciences
- Medical Research Council
- Prostate Cancer UK
- Prostate Cancer Foundation
- Movember Foundation through the London Movember Centre of Excellence [CEO13_2-002]
- Stand Up To Cancer
- UK Department of Health through an Experimental Cancer Medicine Centre grant
- US Department of Defense
- MRC [MR/M018318/1] Funding Source: UKRI
- European Research Council (ERC) [683136] Funding Source: European Research Council (ERC)
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This study identifies JMJD6 as critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.
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.
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