JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 15, 2021
- Source ID
- 10.1158/0008-5472.can-20-1807
Entities
People
- Adam Sharp
- Akane Kawamura
- Alec Paschalis
- Ana Ferreira
- Andrea Alimonti
- Anthony Tumber
- Antje Neeb
- Bissan Al-Lazikani
- Bora Gurel
- Christopher J. Schofield
- Daniel Nava Rodrigues
- Ines Figueiredo
- Johann de Bono
- Jonathan Welti
- Juan M. Jimenez-vacas
- Lorenzo Buroni
- Marc A. Moesser
- Martine I. Abboud
- Maryou B. Lambros
- Mateus Crespo
- Md. Saiful Islam
- Nina Tunariu
- Patrizio Di Micco
- Rita Pereira
- Rossitza Christova
- Ruth Riisnaes
- Soojin Kim
- Stephen R Plymate
- Susana Miranda
- Suzanne Carreira
- Takuma Uo
- Veronica Gil
- Yuan Wei
Organizations
- Cancer Research UK
- ETH Zurich
- European Research Council
- Prostate Cancer Foundation
- Prostate Cancer UK
- Swiss National Science Foundation
- United States Department of Defense
- University of Córdoba
- University of Oxford
- University of Padua
- University of Washington
- Università della Svizzera italiana
- Wellcome Trust