Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/90727
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Type: Journal article
Title: Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies
Author: Chan, S.
Selth, L.
Li, Y.
Nyquist, M.
Miao, L.
Bradner, J.
Raj, G.
Tilley, W.
Dehm, S.
Citation: Nucleic Acids Research, 2015; 43(12):5880-5897
Publisher: Oxford University Press (OUP)
Issue Date: 2015
ISSN: 1362-4962
1362-4962
Statement of
Responsibility: 
Siu Chiu Chan, Luke A. Selth, Yingming Li, Michael D. Nyquist, Lu Miao, James E. Bradner, Ganesh V. Raj, Wayne D. Tilley and Scott M. Dehm
Abstract: Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.
Keywords: Cell Line; Cell Line, Tumor; Chromatin; Animals; Mice, Nude; Prostatic Neoplasms; Azepines; Triazoles; Phenylthiohydantoin; Receptors, Androgen; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Response Elements; Dimerization; Drug Resistance, Neoplasm; Male; Transcriptional Activation; Prostatic Neoplasms, Castration-Resistant
Description: First published online: April 23, 2015
Rights: © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
RMID: 0030027676
DOI: 10.1093/nar/gkv262
Appears in Collections:Medicine publications

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