Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

Siu Chiu Chan, Luke A. Selth, Yingming Li, Michael D. Nyquist, Lu Miao, James E. Bradner, Ganesh V. Raj, Wayne D. Tilley, Scott M. Dehm

Research output: Contribution to journalArticle

84 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5880-5897
Number of pages18
JournalNucleic Acids Research
Volume43
Issue number12
DOIs
StatePublished - 2015

Fingerprint

Androgen Receptors
Chromatin
Prostatic Neoplasms
Therapeutics
Circulating Neoplastic Cells
Chromatin Immunoprecipitation
Dimerization
Response Elements
Transcriptional Activation
Androgens
Transcription Factors

ASJC Scopus subject areas

  • Genetics

Cite this

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. / Chan, Siu Chiu; Selth, Luke A.; Li, Yingming; Nyquist, Michael D.; Miao, Lu; Bradner, James E.; Raj, Ganesh V.; Tilley, Wayne D.; Dehm, Scott M.

In: Nucleic Acids Research, Vol. 43, No. 12, 2015, p. 5880-5897.

Research output: Contribution to journalArticle

Chan, Siu Chiu ; Selth, Luke A. ; Li, Yingming ; Nyquist, Michael D. ; Miao, Lu ; Bradner, James E. ; Raj, Ganesh V. ; Tilley, Wayne D. ; Dehm, Scott M. / Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 12. pp. 5880-5897.
@article{94113e5a9f06404e9be2567299fe454d,
title = "Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies",
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.",
author = "Chan, {Siu Chiu} and Selth, {Luke A.} and Yingming Li and Nyquist, {Michael D.} and Lu Miao and Bradner, {James E.} and Raj, {Ganesh V.} and Tilley, {Wayne D.} and Dehm, {Scott M.}",
year = "2015",
doi = "10.1093/nar/gkv262",
language = "English (US)",
volume = "43",
pages = "5880--5897",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

AU - Chan, Siu Chiu

AU - Selth, Luke A.

AU - Li, Yingming

AU - Nyquist, Michael D.

AU - Miao, Lu

AU - Bradner, James E.

AU - Raj, Ganesh V.

AU - Tilley, Wayne D.

AU - Dehm, Scott M.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84942163753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942163753&partnerID=8YFLogxK

U2 - 10.1093/nar/gkv262

DO - 10.1093/nar/gkv262

M3 - Article

C2 - 25908785

AN - SCOPUS:84942163753

VL - 43

SP - 5880

EP - 5897

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 12

ER -