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Series GSE55062 Query DataSets for GSE55062
Status Public on Apr 25, 2014
Title Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.
Overall design Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors
Contributor(s) Cieslik M, Asangani IA
Citation(s) 24759320
Submission date Feb 14, 2014
Last update date May 15, 2019
Contact name Marcin Piotr Cieslik
Organization name University of Michigan
Department Pathology
Street address 500 S State St
City Ann Arbor
State/province Michigan
ZIP/Postal code 48104
Country USA
Platforms (1)
GPL15433 Illumina HiSeq 1000 (Homo sapiens)
Samples (35)
GSM1328945 AR_vehicle control _exp1
GSM1328947 AR_vehicle control _exp2
GSM1328950 AR_DHT_exp1
This SubSeries is part of SuperSeries:
GSE55064 Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer
BioProject PRJNA238361
SRA SRP037993

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Supplementary file Size Download File type/resource
GSE55062_RAW.tar 16.3 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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