JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.

Autor:	Paschalis A; The Institute of Cancer Research, London, United Kingdom.; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Welti J; The Institute of Cancer Research, London, United Kingdom., Neeb AJ; The Institute of Cancer Research, London, United Kingdom., Yuan W; The Institute of Cancer Research, London, United Kingdom., Figueiredo I; The Institute of Cancer Research, London, United Kingdom., Pereira R; The Institute of Cancer Research, London, United Kingdom., Ferreira A; The Institute of Cancer Research, London, United Kingdom., Riisnaes R; The Institute of Cancer Research, London, United Kingdom., Rodrigues DN; The Institute of Cancer Research, London, United Kingdom., Jiménez-Vacas JM; Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Cordoba, Spain.; Hospital Universitario Reina Sofía (HURS), Cordoba, Spain., Kim S; Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, Washington., Uo T; Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, Washington., Micco PD; The Institute of Cancer Research, London, United Kingdom., Tumber A; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Islam MS; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Moesser MA; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Abboud M; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Kawamura A; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Gurel B; The Institute of Cancer Research, London, United Kingdom., Christova R; The Institute of Cancer Research, London, United Kingdom., Gil VS; The Institute of Cancer Research, London, United Kingdom., Buroni L; The Institute of Cancer Research, London, United Kingdom., Crespo M; The Institute of Cancer Research, London, United Kingdom., Miranda S; The Institute of Cancer Research, London, United Kingdom., Lambros MB; The Institute of Cancer Research, London, United Kingdom., Carreira S; The Institute of Cancer Research, London, United Kingdom., Tunariu N; The Institute of Cancer Research, London, United Kingdom.; The Royal Marsden NHS Foundation Trust, London, United Kingdom., Alimonti A, Al-Lazikani B; The Institute of Cancer Research, London, United Kingdom., Schofield CJ; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom., Plymate SR; Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, Washington., Sharp A; The Institute of Cancer Research, London, United Kingdom.; The Royal Marsden NHS Foundation Trust, London, United Kingdom., de Bono JS; The Institute of Cancer Research, London, United Kingdom. johann.de-bono@icr.ac.uk.; The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Feb 15; Vol. 81 (4), pp. 1087-1100.
DOI:	10.1158/0008-5472.CAN-20-1807
Abstrakt:	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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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