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| Status |
Public on Sep 03, 2019 |
| Title |
Molecular determinants for enzalutamide-induced transcription in prostate cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Enzalutamide, a second-generation androgen receptor (AR) antagonist, has demonstrated clinical benefit in men with prostate cancer. However, it only provides a temporary response and modest increase in survival, indicating a rapid evolution of resistance. Previous studies suggest that enzalutamide may function as a partial transcriptional agonist, but the underlying mechanisms for enzalutamide-induced transcription remain poorly understood. Here, we show that enzalutamide stimulates expression of a novel subset of genes distinct from androgen-responsive genes. Treatment of prostate cancer cells with enzalutamide enhances recruitment of pioneer factor GATA2, AR, Mediator subunits MED1 and MED14, and RNA Pol II to regulatory elements of enzalutamide-responsive genes. Mechanistically, GATA2 functions in directing AR, Mediator and Pol II loading to enzalutamide-responsive gene loci. Importantly, the GATA2 inhibitor K7174 inhibits enzalutamide-induced transcription by decreasing binding of the GATA2/AR/Mediator/Pol II transcriptional complex, contributing to sensitization of prostate cancer cells to enzalutamide treatment. Our findings provide mechanistic insight into the future combination of GATA2 inhibitors and enzalutamide for improved AR-targeted therapy.
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| Overall design |
mRNA profiles of LNCaP cells treated with vehicle, DHT and Enzalutamide were generated by deep sequencing, in duplicate, using Illumina HiSeq2500
mRNA profiles of LNCaP cells (sicontrol or siGATA2) treated with vehicle and Enzalutamide were generated by deep sequencing, in triplicate, using Illumina HiSeq4000
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| Contributor(s) |
Chen Z, Yuan F, Wang Q |
| Citation(s) |
31501863 |
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| Submission date |
Jan 13, 2019 |
| Last update date |
Dec 03, 2019 |
| Contact name |
Zhong Chen |
| E-mail(s) |
zhong.chen128@duke.edu
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| Organization name |
Duke University
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| Department |
Pathology
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| Lab |
Room 1027B, GSRB1
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| Street address |
905 S. LaSalle Street
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| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27710 |
| Country |
USA |
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| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA514909 |
| SRA |
SRP178865 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE125014_LNCaP_DHT_24h_gene.read.counts.txt.gz |
166.8 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_DHT_4h_gene.read.counts.txt.gz |
168.9 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_MDV_24h_gene.read.counts.txt.gz |
167.7 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_MDV_4h_gene.read.counts.txt.gz |
166.7 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_Vehicle_gene.read.counts.txt.gz |
242.7 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_siGATA2_MDV_gene.read.counts.txt.gz |
298.9 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_siGATA2_vehicle_gene.read.counts.txt.gz |
298.8 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_sicontrol_vehicle_gene.read.counts.txt.gz |
299.9 Kb |
(ftp)(http) |
TXT |
| GSE125014_LNCaP_sincontrol_MDV_gene.read.counts.txt.gz |
297.8 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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