Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer
- Dana-Farber Cancer Institute, United States
- Institute of Cancer Research, United Kingdom
- The Barcelona Institute of Science and Technology, Spain
- Karlsruhe Institute of Technology, Germany
- Innsbruck Medical University, Austria
- The Institute of Cancer Research, United Kingdom
- Dana-Farber Cancer Instittue, United States
Abstract
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.
Data availability
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Targeting the androgen receptor N-terminus via the cochaperone Bag-1LPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE89939).
Article and author information
Author details
Gerd Ulrich Nienhaus
Funding
Prostate Cancer Foundation
- Laura Cato
- Adam Sharp
- Johann S de Bono
- Andrew CB Cato
- Myles Brown
Deutsche Krebshilfe
- Andrew CB Cato
Barr Foundation
- Laura Cato
Prostate Cancer UK
- Adam Sharp
Medical Research Council
- Adam Sharp
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Chi Van Dang, University of Pennsylvania, United States
Version history
- Received: March 23, 2017
- Accepted: August 7, 2017
- Accepted Manuscript published: August 10, 2017 (version 1)
- Version of Record published: October 5, 2017 (version 2)
Copyright
© 2017, Cato et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer
eLife 6:e27159.
https://doi.org/10.7554/eLife.27159
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