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

被引：1

作者：

Kanno, Yuichiro ^{[1
,2
]}

Saito, Nao ^{[2
]}

Saito, Ryota ^{[4
]}

Kosuge, Tomohiro ^{[1
]}

Shizu, Ryota ^{[1
]}

Yatsu, Tomofumi ^{[2
]}

Hosaka, Takuomi ^{[1
]}

Nemoto, Kiyomitsu ^{[2
]}

Kato, Keisuke ^{[3
]}

Yoshinari, Kouichi ^{[1
]}

机构：

[1] Univ Shizuoka, Sch Pharmaceut Sci, Lab Mol Toxicol, 52-1 Yada,Suruga Ku, Shizuoka 4228526, Japan

[2] Toho Univ, Fac Pharmaceut Sci, Dept Mol Toxicol, Miyama 2-2-1, Funabashi, Chiba 2748510, Japan

[3] Toho Univ, Fac Pharmaceut Sci, Dept Organ Chem, 2-2-1 Miyama, Funabashi, Chiba 2748510, Japan

[4] Toho Univ, Dept Chem, 2-2-1 Miyama, Funabashi, Chiba 2748510, Japan

来源：

EXPERIMENTAL CELL RESEARCH | 2022年 / 419卷 / 02期

基金：

日本学术振兴会;

关键词：

Nuclear receptor; Androgen receptor; Breast cancer; Selective androgen receptor modulator; PROTEIN-LIGAND DOCKING; MEDIATED REGULATION; FUNCTIONAL-ANALYSIS; NATURAL AGONIST; PROSTATE-CANCER; REGULATED GENE; ACTIVATION; DOMAIN; MUTATION; YK11;

D O I：

10.1016/j.yexcr.2022.113333

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 trans -activation. 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.

引用

页数：10