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AR regulated transcriptome in prostate cancer cells

ABSTRACT: It has been well established that the transcription factor androgen receptor (AR) is obligatory for prostate cancer (PCa) development and progression, but the precise role of the AR in these processes is still unclear. To dissect the role of AR in shaping the transcriptome of prostate cancer cells, RNA-seq data were obtained from AR-positive LNCaP cells treated with various regimens to manipulate endogenous AR signaling. LNCaP cells were cultured in normal medium containing fetal bovine serum (FBS) to represent an androgen-dependent (AD) growth state. To mimic the clinical androgen-deprivation-therapy (ADT) settings, cells were grown for 4 days in conditions of either depletion of androgen (i.e., medium containing charcoal:dextran stripped fetal bovine serum (CDSS)) or the presence of AR antagonist Enzalutamide (MDV3100, 10 μM) to represent androgen-independent (AI) growth states. Aside from the pharmaceutical modulations, we also utilized siRNA to knockdown AR. To examine the direct effects of AR signaling on gene transcription and splicing, cells were primed with CDSS for 3 days followed by treatment of 10nM dihydrotestosterone (DHT) for 8-9 hrs. Deep sequencing of rRNA-depleted total RNAs was performed in biological duplicates on abovementioned LNCaP cultures.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114052 | GEO | 2020/03/04

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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AR regulated transcriptome in prostate cancer cells

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