Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.
eLife. 2017 Aug 10*** epublish ***
Laura Cato, Antje Neeb, Adam Sharp, Victor Buzón, Scott B Ficarro, Linxiao Yang, Claudia Muhle-Goll, Nane C Kuznik, Ruth Riisnaes, Daniel Nava Rodrigues, Olivier Armant, Victor Gourain, Guillaume Adelmant, Emmanuel A Ntim, Thomas Westerling, David Dolling, Pasquale Rescigno, Ines Figueiredo, Friedrich Fauser, Jennifer Wu, Jaice T Rottenberg, Liubov Shatkina, Claudia Ester, Burkhard Luy, Holger Puchta, Jakob Troppmair, Nicole Jung, Stefan Bräse, Uwe Strähle, Jarrod A Marto, Gerd Ulrich Nienhaus, Bissan Al-Lazikani, Xavier Salvatella, Johann S de Bono, Andrew Cb Cato, Myles Brown
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States., Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany., Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom., Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain., The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States., Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany., Institute for Biological Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany., Clinical Trials and Statistics Unit, Institute of Cancer Research, London, United Kingdom., Botanical Institute II, Karlsruhe Institute of Technology, Karlsruhe, Germany., Daniel-Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria., Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany., Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.