Sequence specific suppression of androgen receptor–DNA binding in vivo by a Py-Im polyamide
The crucial role of androgen receptor (AR) in prostate cancer development is well documented, and its inhibition is a mainstay of prostate cancer treatment. Here, we analyze the perturbations to the AR cistrome caused by a minor groove binding molecule that is designed to target a sequence found in a subset of androgen response elements (ARE). We find treatment with this pyrrole-imidazole (Py-Im) polyamide exhibits sequence selectivity in its repression of AR binding in vivo. Differentially changed loci are enriched for sequences resembling ARE half-sites that match the Py-Im polyamide binding preferences determined in vitro. Comparatively, permutations of the ARE half-site bearing single or double mismatches to the Py-Im polyamide binding sequence are not enriched. This study confirms that the in vivo perturbation pattern caused by a sequence specific polyamide correlates with its in vitro binding preference genome-wide in an unbiased manner.
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 24 January 2019; Revision Received: 20 February 2019; Accepted: 22 February 2019; Published: 06 March 2019. Data Availability: Data deposited in GEO: series GSE125552. The authors thank the veterinary staff at Caltech for all their assistance, particularly Gloria Martinez for performing the castration surgeries, and Gwen Williams and John Papsys for monitoring animal health. Sequencing was performed at the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology, and confocal imaging was performed at the Caltech Biological Imaging Facility. Funding: National Institutes of Health [GM027681 to P.B.D., T32GM761637 to A.A.K.]; Ralph M. Parsons Foundation graduate fellowship (to A.A.K.). Funding for open access charge: National Institutes of Health grant [GM027681]. Conflict of interest statement. One of the authors in this study, P.B.D., holds shares in a privately held entity focused on developing Py-Im polyamides for the treatment of antiandrogen resistant prostate cancer.
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