RT Journal Article
T1 JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
A1 Paschalis, Alec
A1 Welti, Jonathan
A1 Neeb, Antje J
A1 Yuan, Wei
A1 Figueiredo, Ines
A1 Pereira, Rita
A1 Ferreira, Ana
A1 Riisnaes, Ruth
A1 Rodrigues, Daniel Nava
A1 Jimenez-Vacas, Juan M
A1 Kim, Soojin
A1 Uo, Takuma
A1 Micco, Patrizio Di
A1 Tumber, Anthony
A1 Islam, Md Saiful
A1 Moesser, Marc A
A1 Abboud, Martine
A1 Kawamura, Akane
A1 Gurel, Bora
A1 Christova, Rossitza
A1 Gil, Veronica S
A1 Buroni, Lorenzo
A1 Crespo, Mateus
A1 Miranda, Susana
A1 Lambros, Maryou B
A1 Carreira, Suzanne
A1 Tunariu, Nina
A1 Alimonti, Andrea
A1 Al-Lazikani, Bissan
A1 Schofield, Christopher J
A1 Plymate, Stephen R
A1 Sharp, Adam
A1 de Bono, Johann S
K1 Alternative splicing
K1 Antineoplastic agents
K1 Cell line, tumor
K1 Cohort studies
K1 Enzyme inhibitors
K1 Gene expression regulation, neoplastic
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.
PB American Association for Cancer Research
YR 2020
FD 2020-12-02
LK http://hdl.handle.net/10668/17533
UL http://hdl.handle.net/10668/17533
LA en
NO Paschalis A, Welti J, Neeb AJ, Yuan W, Figueiredo I, Pereira R, et al. JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer. Cancer Res. 2021 Feb 15;81(4):1087-1100
NO Research supported by an Stand Up To CancerProstate Cancer Dream Team Translational Research Grant (SU2C-AACRDT0712). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. This research was funded by Cancer Research UK and a Prostate Cancer UK Research Innovation Award (RIA17-ST2-014). A. Alimonti was supported by European Research Council Consolidator Grant (683136); Swiss Cancer League (4267); Swiss National Science Foundation (176045); Prostate Cancer Foundation (19CHAL08); and Italian Association for Cancer Research Investigator Grant (22030). C.J. Schofield and A. Kawamura thank CRUK (C8717/A18245) and the Wellcome Trust (106244/Z/14/Z) for funding. S.R. Plymate gratefully acknowledgesDOD Grants W81XWH-17-0323 and W81XWH-20-0146 (S.R. Plymate) and DOD W81XWH-17-0414 (S.R. Plymate) and Veterans Affairs Research Service Merit Award and Senior Clinician Scientist Research Award. A. Sharp also gratefully acknowledges previous research funding from the Academy of Medical Sciences, the Medical Research Council, and Prostate Cancer UK, and current funding from the Prostate Cancer Foundation and Wellcome Trust. J.S. de Bono also gratefully acknowledges research funding from Prostate Cancer UK and the Movember Foundation through the London Movember Centre of Excellence (CEO13_2-002), the Prostate Cancer Foundation, Stand Up To Cancer, the UK Department of Health through an Experimental Cancer Medicine Centre grant, and the US Department of Defense. Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
DS RISalud
RD Apr 11, 2025