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.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.
authors.forename: Siu Chiu
authors.initials: SC
authors.lastname: Chan
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Mens' Health, School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Selth
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55905, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Nyquist
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Miao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Mens' Health, School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55905, USA dehm@umn.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Dehm
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001381:Azepines / Q000494:pharmacology; D001549:Benzamides; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D019281:Dimerization; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008297:Male; D008819:Mice, Nude; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015533:Transcriptional Activation / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; D001549:Benzamides; D002843:Chromatin; D009570:Nitriles; D011944:Receptors, Androgen; D014230:Triazoles; D010669:Phenylthiohydantoin; C540278:enzalutamide