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Series GSE103449 Query DataSets for GSE103449
Status Public on Sep 11, 2017
Title Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.
Overall design A total of 45 samples were analyzed (905L = LNAR'; 924R = LREX'). For ChIP-seq, histone modification (H3K4me1, H3K4me3, H3K27ac, H3K27me3) ChIP and BRD4 ChIP was performed on cell lines with or without Enz treatment; input used to normalize. Chem-Seq using bio-JQ1 was performed on cell lines with or without Enz treatment. RNA-seq was performed on in vivo LNAR' or LREX' tumors treated with vehicle or JQ1 (n=4 tumors analyzed per treatment condition)
Contributor(s) Shah N, Sawyers CL, Wang P, Zheng D
Citation(s) 28891793
Submission date Sep 05, 2017
Last update date May 15, 2019
Contact name Deyou Zheng
Organization name Albert Einstein College of Medicine
Street address 1301 Morris Park Ave
City Bronx
State/province NY
ZIP/Postal code 10461
Country USA
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (41)
GSM2771573 LNAR_H3K27ac_ChIPSeq
GSM2771574 LREX_H3K27ac_ChIPSeq
GSM2771575 LREXEnz_H3K27ac_ChIPSeq
BioProject PRJNA401755
SRA SRP117044

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Supplementary file Size Download File type/resource
GSE103449_RAW.tar 5.2 Gb (http)(custom) TAR (of TDF)
GSE103449_counts_RNASeq.txt.gz 840.3 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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