Inhibition of p53 expression modifies the specificity of chromatin binding by the androgen receptor

Natalya V Guseva; Oskar W Rokhlin; Thomas B Bair; Rebecca B Glover; Michael B Cohen

doi:10.18632/oncotarget.449

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Inhibition of p53 expression modifies the specificity of chromatin binding by the androgen receptor

Journal article

Open access

Peer reviewed

Inhibition of p53 expression modifies the specificity of chromatin binding by the androgen receptor

Natalya V Guseva, Oskar W Rokhlin, Thomas B Bair, Rebecca B Glover and Michael B Cohen

Oncotarget, Vol.3(2), pp.183-194

02/29/2012

DOI: 10.18632/oncotarget.449

PMCID: PMC3326648

PMID: 22383394

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Abstract

The androgen receptor (AR) is known to play a critical role in prostate cancer (PC). p53 likely also plays a role given that p53 mutations are commonly found in advanced PC, and loss of wild-type protein function contributes to the phenotype of castration-resistant prostate cancer (CRPC). Nevertheless, the extent of the contribution of p53 dysfunction to PC remains unclear. Here we analyze the effects of p53 inhibition in PC cells and show that it has significant consequences for both the interaction between AR, and chromatin and the proliferative capacity of these cells. Inhibition of p53 expression enabled LNCaP cells to proliferate independently of androgens. Moreover, it modified the genome-wide binding pattern of AR. ChIP-sequnce analyis (ChIP-seq) revealed that fewer AR-binding sites were present in the context of p53 inhibition, suggesting that wild-type p53 is required for stable binding of AR to certain chromatin regions. Further analysis revealed that a lower AR occupancy was accompanied by a reduction in FoxA1 binding at regulatory regions of AR-dependent genes. Our study also identifies a pool of genes that may be transcriptionally regulated by AR only in the absence of p53, and that may contribute to the CRPC phenotype. Overall, our results point to p53 playing an important role in regulating AR activity across the genome.

Cell Line, Tumor

Cell Proliferation

Chromatin - metabolism

Gene Expression Profiling

Gene Expression Regulation, Neoplastic

Hepatocyte Nuclear Factor 3-alpha - metabolism

Humans

Male

Prostatic Neoplasms - genetics

Prostatic Neoplasms - metabolism

Protein Binding

Receptors, Androgen - genetics

Receptors, Androgen - metabolism

Tumor Suppressor Protein p53 - antagonists & inhibitors

Tumor Suppressor Protein p53 - metabolism

Details

Title: Subtitle: Inhibition of p53 expression modifies the specificity of chromatin binding by the androgen receptor
Creators: Natalya V Guseva - University of Iowa Hospitals and Clinics
Oskar W Rokhlin - University of Iowa
Thomas B Bair - University of Iowa
Rebecca B Glover - University of Iowa
Michael B Cohen - University of Iowa
Resource Type: Journal article
Publication Details: Oncotarget, Vol.3(2), pp.183-194
DOI: 10.18632/oncotarget.449
PMID: 22383394
PMCID: PMC3326648
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: Impact Journals LLC
Language: English
Date published: 02/29/2012
Academic Unit: Pathology
Record Identifier: 9984647058602771

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