Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
Nucleic Acids Res. 2019 May 7;47(8):3828-3835. doi: 10.1093/nar/gkz153.
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.
雄激素受体（AR）在前列腺癌发展中的关键作用已有充分的文献记载，其抑制作用是前列腺癌治疗的主要手段。在这里，我们分析了一种设计用于靶向雄激素反应元件（ARE）亚组中发现的序列的小沟结合分子对 AR 顺式作用元件的扰动。我们发现，用这种吡咯-咪唑（Py-Im）聚酰胺处理会在体内抑制 AR 结合时表现出序列选择性。差异变化的基因座富含与体外确定的 Py-Im 聚酰胺结合偏好相匹配的类似于 ARE 半位点的序列。相比之下，与 Py-Im 聚酰胺结合序列有单个或两个错配的 ARE 半位点的排列并不丰富。这项研究证实，一种序列特异性聚酰胺在体内引起的扰动模式与其在全基因组范围内的体外结合偏好是一致的，且是无偏的。
