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| Status |
Public on Mar 07, 2018 |
| Title |
Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression [RNA-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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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| Overall design |
Androgen receptor splice variants (AR-V1, AR-V3, AR-V4 and AR-V7) were knocked down using siRNA in 22Rv1 cells (siARVs). RNA-seq experiments were then performed for both siARVs and control (siNT) samples in duplicates. Differentially expressed genes were identified by comparing siARVs with siNT.
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| Contributor(s) |
Wang L, Ye Z, Lu J |
| Citation(s) |
29309643 |
| |
| Submission date |
Apr 28, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Zhenqing Ye |
| E-mail(s) |
iamyezhenqing@gmail.com
|
| Organization name |
UT Health San Antonio
|
| Department |
6Department of Population Health Sciences
|
| Street address |
8403 Floyd Curl Dr
|
| City |
San Antonio |
| State/province |
TX |
| ZIP/Postal code |
78229 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE80743 |
Identification and characterization of androgen receptor splice variants preferred bindings that drive prostate cancer progression |
|
| Relations |
| BioProject |
PRJNA319902 |
| SRA |
SRP074099 |
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