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| Status |
Public on Jan 01, 2009 |
| Title |
Effect of individual HDAC knockdown on expression of androgen induced genes |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition.
Keywords: Androgen receptor, histone deacetylase, prostate cancer, dose response
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| Overall design |
Lentiviral shRNA mediated knockdown of Luciferase (ctrl), HDAC1, HDAC2, and HDAC8 LnCAP cells were generated. They were grown in charcoal stripped, androgen deplete medium. They were then stimulated with or without 1nM R1881. Cyclohexamide was include to block new protein synthesis. Cells were harvested 16 hours after treatment.
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| Contributor(s) |
Welsbie DS, Xu J, Chen Y, Borsul L, Scher HI, Rosen N, Sawyers CL |
| Citation(s) |
19176386 |
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| Submission date |
Aug 13, 2008 |
| Last update date |
Dec 06, 2018 |
| Contact name |
Yu Chen |
| E-mail(s) |
cheny1@mskcc.org
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| Phone |
646-888-3356
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Department |
Human Oncology and Pathogenesis Program
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| Lab |
Chen
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| Street address |
1275 York Ave, Box 20
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
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| Samples (20)
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| GSM312326 |
Luciferase KD, 1nM R1881, rep2 |
| GSM312327 |
HDAC1 KD, No R1881, rep1 |
| GSM312328 |
HDAC1 KD, No R1881, rep2 |
| GSM312329 |
HDAC1 KD, 1nM R1881, rep1 |
| GSM312330 |
HDAC1 KD, 1nM R1881, rep2 |
| GSM312331 |
HDAC2 KD, No R1881, rep1 |
| GSM312332 |
HDAC2 KD, No R1881, rep2 |
| GSM312333 |
HDAC2 KD, 1nM R1881, rep1 |
| GSM312334 |
HDAC2 KD, 1nM R1881, rep2 |
| GSM312335 |
HDAC3 KD, No R1881, rep1 |
| GSM312336 |
HDAC3 KD, No R1881, rep2 |
| GSM312337 |
HDAC3 KD, 1nM R1881, rep1 |
| GSM312338 |
HDAC3 KD, 1nM R1881, rep2 |
| GSM312339 |
HDAC8 KD, No R1881, rep1 |
| GSM312340 |
HDAC8 KD, No R1881, rep2 |
| GSM312341 |
HDAC8 KD, 1nM R1881, rep1 |
| GSM312342 |
HDAC8 KD, 1nM R1881, rep2 |
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| Relations |
| BioProject |
PRJNA112989 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE12438_RAW.tar |
187.5 Mb |
(http)(custom) |
TAR (of CEL, CHP, EXP) |
| Processed data included within Sample table |
| Processed data provided as supplementary file |
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