Sequence specific suppression of androgen receptor-DNA binding in vivo by a Py-Im polyamide.

Alexis A Kurmis,Peter B Dervan

doi:10.1093/nar/gkz153

Abstract

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.

Highlights

Transcription factors regulate cellular gene expression and the loss of this regulatory balance can lead to a myriad of genetic diseases including cancer
We further evaluate the activity of ARE1 in LNCaP-95 cells, which derive their resistance from the expression of androgen receptor (AR) splice variants [37]
Antiproliferative effect of androgen response elements (ARE)-1 toward LNCaP-95 cell growth was evaluated using the CTG assay and compared against the antiandrogen enzalutamide and pyrvinium pamoate, a molecule that has been reported to bind to the AR DNAbinding domain to prevent AR–DNA interactions [38]

Summary

Introduction

Transcription factors regulate cellular gene expression and the loss of this regulatory balance can lead to a myriad of genetic diseases including cancer. The role of androgen receptor (AR) in prostate cancer is one of the most well characterized examples. Work in 1941 by Charles Huggins and Clarence Hodges showed that the progression of prostate cancer can be controlled by androgen deprivation through castration or hormonal therapy with estrogen [1]. The AR has remained the primary target for systemic therapeutics for prostate cancer patients [3,4]. Newer anti-androgens including enzalutamide and apalutamide have already been approved and others are in late-stage clinical development [5,6,7]

Methods

Results

Conclusion