E-GEOD-55062 - Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)

Status
Released on 25 April 2014, last updated on 1 June 2014
Organism
Homo sapiens
Samples (35)
Protocols (4)
Description
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. Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors
Experiment type
ChIP-seq 
Contacts
Marcin Piotr Cieslik <marcin.cieslik@gmail.com>, Irfan A Asangani, Marcin Cieslik
Citation
Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, Iyer MK, Jing X, Wu YM, Cao X, Qin ZS, Wang S, Feng FY, Chinnaiyan AM. , Europe PMC 24759320
MINSEQE
Exp. designProtocolsFactorsProcessedSeq. reads
Files
Investigation descriptionE-GEOD-55062.idf.txt
Sample and data relationshipE-GEOD-55062.sdrf.txt
Processed data (26)Click to browse processed data
Links