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Series GSE12438 Query DataSets for GSE12438
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
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
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.
Contributor(s) Welsbie DS, Xu J, Chen Y, Borsul L, Scher HI, Rosen N, Sawyers CL
Citation(s) 19176386
Submission date Aug 13, 2008
Last update date Dec 06, 2018
Contact name Yu Chen
Phone 646-888-3356
Organization name Memorial Sloan Kettering Cancer Center
Department Human Oncology and Pathogenesis Program
Lab Chen
Street address 1275 York Ave, Box 20
City New York
State/province NY
ZIP/Postal code 10065
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (20)
GSM312323 Luciferase KD, No R1881, rep1
GSM312324 Luciferase KD, No R1881, rep2
GSM312325 Luciferase KD, 1nM R1881, rep1
BioProject PRJNA112989

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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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