Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes

Abstract

Constitutively-active androgen receptor splice variants (AR-V) lacking the ligand-binding domain have been implicated in the pathogenesis of castration-resistant prostate cancer and in mediating resistance to newer drugs that target the androgen axis. AR-V regulate expression of both canonical AR targets and a unique set of cancer-specific targets that are enriched for cell cycle functions. However, little is known about how AR-V control gene expression. Here we report that two major AR-V, termed AR-V7 and ARv567es, not only homodimerize and heterodimerize with each other but also heterodimerize with full-length androgen receptor (AR-FL) in an androgen-independent manner. We found that heterodimerization of AR-V and AR-FL was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions. Notably, AR-V dimerization was required to transactivate target genes and to confer castration-resistant cell growth. Our results clarify the mechanism by which AR-V mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling, as a rational strategy for effective treatment of advanced prostate cancer.

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

“…Interestingly, a growing body of literature suggests that these truncated AR variants require functional full-length AR (FL-AR) to mediate drug resistance. Specifically, the AR variants AR-V7 and AR v567es have been shown to heterodimerize with FL-AR, enable its nuclear localization, and facilitate the expression of canonical AR target genes (15,16). Similarly, simultaneous antisense-oligo-mediated down-regulation of AR-V7 and FL-AR offers no additional benefit over FL-AR down-regulation alone in enzalutamide-resistant LnCaP-derived xenografts (17).…”

Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

“…The extent to which the spectrum of molecular alterations acquired after first-line therapy contributed to resistance in this new treatment setting remains largely uncharacterized (49). Constitutively active AR-Vs, such as AR-V7, lacking the LBD have been implicated in the pathogenesis of CRPC and in mediating resistance to newer drugs that target the androgen axis (50). In our studies, FLII inhibited AR transactivation and modulated AR cytoplasm/nucleus localization through direct binding to AR-LBD.…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…First, a recent study from our group found that AR-FL and ARv567es cistromes were highly concordant, with both exhibiting a preference for canonical inverted repeat androgen response elements (Chan et al 2015). Second, dimerization of AR-Vs is required for their transcriptional activity and utilizes the same interaction surface as AR-FL (Chan et al 2015, Xu et al 2015. Finally, transcriptional repression of AR-Vs by binding of the transcription factor FOXO1 to transcription activation unit 5 (TAU5) in the NTD revealed that, like AR-FL, they require this domain for transcriptional activity.…”

“…The finding that AR-Vs can heterodimerize with AR-FL or with other AR-Vs , Cao et al 2014, Xu et al 2015 raises the possibility that the nature and relative expression of different AR-Vs and AR-FL in single cells could influence distinct transcriptional outputs.…”