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Functional characterization of androgen receptor dimerization interfaces [RNA-seq]

ABSTRACT: The activity of the androgen receptor (AR) is thought to rely on interactions between its functional domains, including dimerization of the DNA-binding domain (DBD), the ligand-binding domain (LBD), and the N-terminal domain (NTD) with the LBD (N/C interaction). However, their contributions to genome-wide AR signaling remain unclear. Using U2OS cell lines expressing AR mutants that selectively disrupt each dimerization interface, we dissected their roles in transactivation, chromatin binding, cofactor recruitment, and transcriptional regulation. The disruption of LBD dimerization or N/C interactions had limited effects. Both AR mutants largely preserved enhancer activity, chromatin occupancy, AR-associated interactomes and androgen-responsive transcriptional programs. In contrast, disruption of DBD dimerization profoundly rewired AR function. Although this mutant lost binding to many AR chromatin sites and attenuated the classical androgen-responsive transcriptome, it also retained activity at a subset of loci. In addition, it gained binding at new chromatin regions enriched for half-site androgen response elements and other transcription factor motifs. RUNX factors, whose binding motifs were among the enriched motifs, directly contributed to part of the altered AR program. These data identify DBD dimerization as the principal determinant of canonical AR signaling, while revealing that monomeric DNA-binding of AR adopts alternative, cofactor-assisted chromatin-binding strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE333539 | GEO | 2026/05/27

REPOSITORIES: GEO

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Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.

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Functional characterization of androgen receptor dimerization interfaces [RNA-seq]

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