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Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

Nickols, Nicholas G. and Dervan, Peter B. (2007) Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide. Proceedings of the National Academy of Sciences of the United States of America, 104 (25). pp. 10418-10423. ISSN 0027-8424. PMCID PMC1965528. https://resolver.caltech.edu/CaltechAUTHORS:NICpnas07

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Abstract

Androgen receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen (PSA) promoter androgen response element, inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1965528/PubMed CentralArticle
http://www.pnas.org/cgi/content/full/0704217104/DC1PublisherSupporting Information
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:Copyright © 2007 by the National Academy of Sciences. Contributed by Peter B. Dervan, May 8, 2007 (received for review April 16, 2007). This work was supported by National Institutes of Health Grant GM57148. Mass spectrometry analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering at the California Institute of Technology, supported in part by the National Science Foundation Materials Research Science and Engineering program. Oligonucleotide microarray experiments were performed in the Millard and Muriel Jacobs Genetics and Genomics Laboratory at the California Institute of Technology. Author contributions: N.G.N. and P.B.D. designed research; N.G.N. performed research; N.G.N. and P.B.D. analyzed data; and N.G.N. and P.B.D. wrote the paper. The authors declare no conflict of interest. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE7708). This article contains supporting information online at www.pnas.org/cgi/content/full/0704217104/DC1.
Funders:
Funding AgencyGrant Number
NIHGM-57148
NSFUNSPECIFIED
Subject Keywords:prostate cancer; bicalutamide; small molecule; transcription
Issue or Number:25
PubMed Central ID:PMC1965528
Record Number:CaltechAUTHORS:NICpnas07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:NICpnas07
Alternative URL:http://dx.doi.org/10.1073/pnas.0704217104
Official Citation:Nicholas G. Nickols and Peter B. Dervan Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide PNAS 2007 104 (25) 10418-10423; published ahead of print June 12, 2007, doi:10.1073/pnas.0704217104
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9408
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:19 Dec 2007
Last Modified:26 Nov 2019 11:15

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