Differential DNA-binding and cofactor recruitment are possible determinants of the synthetic steroid YK11-dependent gene expression by androgen receptor in breast cancer MDA-MB 453?cells
Differential DNA-binding and cofactor recruitment are possible determinants of the synthetic steroid YK11-dependent gene expression by androgen receptor in breast cancer MDA-MB 453?cells
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差异DNA结合和辅因子募集可能是乳腺癌MDA-MB 453细胞中雄激素受体合成类固醇YK11依赖性基因表达的决定因素
DOI：
10.1016/j.yexcr.2022.113333
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发表时间：
2022
影响因子：
3.7
通讯作者：
Yoshinari Kouichi
中科院分区：
文献类型：
--
作者：
Kanno Yuichiro;Saito Nao;Saito Ryota;Kosuge Tomohiro;Shizu Ryota;Yatsu Tomofumi;Hosaka Takuomi;Nemoto Kiyomitsu;Kato Keisuke;Yoshinari Kouichi
最近，选择性雄激素受体调节剂（SARM），结合到AR和组织/效应特异性的方式，已被开发，但选择性机制还没有得到很好的理解。在这项研究中，我们研究了使用合成类固醇YK 11，这表明AR介导的基因选择性反式激活的选择性机制。在AR阳性的人乳腺癌MDA-MB-453细胞中，在DHT和YK 11之间观察到AR介导的靶基因表达和AR募集到其增强子区域的不同模式。对接研究表明，螺旋11和12是由空间位阻的C17-组的YK 11移动。此外，AR Gln 902和哺乳动物双杂交试验的突变研究表明，DHT和YK 11之间存在不同的辅因子募集。这项研究的结果表明，基因选择性调控SARMs的结果从差异DNA结合和/或辅因子招聘配体。这些结果为SARM的作用机制提供了新的见解。
Recently, selective androgen receptor modulators (SARMs), which bind to AR and act in a tissue/effect-specific manner, have been developed, but the selective mechanism is not well understood. In this study, we investigated the selective mechanism using the synthetic steroid YK11, which showed AR-mediated gene-selective transactivation. In the AR-positive human breast cancer MDA-MB-453 cells, different patterns of AR-mediated target gene expression and AR recruitment to their enhancer regions were observed between DHT and YK11. A docking study suggested the helices 11 and 12 was moved by the sterically hindered C17-group of YK11. Furthermore, the mutational studies of AR Gln902 and mammalian two-hybrid assays suggested different cofactor recruitment between DHT and YK11. The results of this study suggest that gene selective regulation by SARMs results from differential DNA-binding and/or cofactor recruitment by ligands. These results provide novel insights into the mechanism of action of SARMs.