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Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80743 | GEO | 2018/03/07

REPOSITORIES: GEO

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Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression [ChIP-seq]

Project description:Androgen receptor (AR) splice variants (ARVs) are implicated in developing castration-resistant (CR) prostate cancer (CRPC). Little is known about the ARV-mediated transcription program in CRPC. We identified ARV-preferred binding sites (ARV-PBS) and unique transcriptome in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions with the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions with the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in CR patients. ARV-driven genes were up-regulated in abiraterone-resistant patient specimens and promote CRPC growth. We uncover distinct genomic and epigenomic characteristics of ARV-PBS and a unique ARV-dependent transcriptional program that not only drives CR progression but could also offer new targets for therapy. Increasing evidence suggests a pivotal role of ARVs in the acquisition of anti-AR therapy resistance in CRPC. It has been shown previously that ARVs possess unique structural and functional features such as completely lacking or only containing an impaired ligand-binding domain but constitutively active. Our findings advance the understanding of ARVs by demonstrating that ARV-PBS exhibit distinctive DNA-binding motif, GC content, and nucleosome and epigenetic characteristics. We further unravel that ARV-PBS exclusively overlap with AR bindings identified from castration-resistant patients and ARV activity is significantly increased in abiraterone-resistant patients. Given that there is no drug available to target ARVs at present, identification of ARV-mediated unique downstream pathways opens new avenues for the development of effective therapeutics for CRPC.

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Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression

Project description:Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression

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