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Elife. 2017 Aug 10;6. pii: e27159. doi: 10.7554/eLife.27159.

Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States.
2
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States.
3
Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
4
Prostate Cancer Target Therapy Group, Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
5
Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
6
The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States.
7
Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
8
Institute for Biological Interfaces, Karlsruhe Institute of Technology, Karlsruhe, Germany.
9
Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany.
10
Institut de Radioprotection et de Sûreté Nucléaire, PRP-ENV/SERIS/LECO, Cadarache, France.
11
Clinical Trials and Statistics Unit, Institute of Cancer Research, London, United Kingdom.
12
Botanical Institute II, Karlsruhe Institute of Technology, Karlsruhe, Germany.
13
Daniel-Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
14
Institute of Nanotechnology, Karlsruhe Institute of Technology, Karlsruhe, Germany.
15
Department of Physics, University of Illinois at Urbana-Champaign, Urbana, United States.
16
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
17
ICREA, Passeig Lluís Companys, Barcelona, Spain.

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.

KEYWORDS:

Bag-1L; androgen receptor; cancer biology; human; prostate cancer; transcription factors

PMID:
28826504
PMCID:
PMC5629025
DOI:
10.7554/eLife.27159
[Indexed for MEDLINE]
Free PMC Article

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