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Series GSE60841 Query DataSets for GSE60841
Status Public on Mar 02, 2015
Title Targeting the MLL complex 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) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), 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 malignancies. 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 JQ1. 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 ASH2L genome-wide binding in prostate cancer cells after AR stimulation.
Contributor(s) Iyer M, Malik R
Citation(s) 25822367
Submission date Aug 27, 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)
GPL10999 Illumina Genome Analyzer IIx (Homo sapiens)
Samples (2)
GSM1489926 vcap_ash2l_veh
GSM1489927 vcap_ash2l_r1881
This SubSeries is part of SuperSeries:
GSE60842 Targeting the MLL complex in castration-resistant prostate cancer
BioProject PRJNA259656
SRA SRP045831

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Supplementary file Size Download File type/resource
GSE60841_RAW.tar 430.4 Mb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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