Park U-H, Kang M-R, Kim E-J, Kwon Y-S, Hur W, Yoon S K, Song B-J, Park J H, Hwang J-T, Jeong J-C, Um S-J
Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Korea.
Oncogene. 2016 Jul 14;35(28):3742-52. doi: 10.1038/onc.2015.443. Epub 2015 Dec 7.
Estrogen receptor alpha (ERα) has a pivotal role in breast carcinogenesis by associating with various cellular factors. Selective expression of additional sex comb-like 2 (ASXL2) in ERα-positive breast cancer cells prompted us to investigate its role in chromatin modification required for ERα activation and breast carcinogenesis. Here, we observed that ASXL2 interacts with ligand E2-bound ERα and mediates ERα activation. Chromatin immunoprecipitation-sequencing analysis supports a positive role of ASXL2 at ERα target gene promoters. ASXL2 forms a complex with histone methylation modifiers including LSD1, UTX and MLL2, which all are recruited to the E2-responsive genes via ASXL2 and regulate methylations at histone H3 lysine 4, 9 and 27. The preferential binding of the PHD finger of ASXL2 to the dimethylated H3 lysine 4 may account for its requirement for ERα activation. On ASXL2 depletion, the proliferative potential of MCF7 cells and tumor size of xenograft mice decreased. Together with our finding on the higher ASXL2 expression in ERα-positive patients, we propose that ASXL2 could be a novel prognostic marker in breast cancer.
雌激素受体α（ERα）通过与多种细胞因子相互作用在乳腺癌发生过程中起关键作用。额外性梳状蛋白样2（ASXL2）在ERα阳性乳腺癌细胞中的选择性表达促使我们研究其在ERα激活和乳腺癌发生所需的染色质修饰中的作用。在此，我们观察到ASXL2与配体E2结合的ERα相互作用并介导ERα激活。染色质免疫沉淀测序分析支持ASXL2在ERα靶基因启动子处的积极作用。ASXL2与包括LSD1、UTX和MLL2在内的组蛋白甲基化修饰因子形成复合物，这些因子均通过ASXL2被招募到E2反应基因并调节组蛋白H3赖氨酸4、9和27处的甲基化。ASXL2的PHD结构域与二甲基化的H3赖氨酸4的优先结合可能解释了其对ERα激活的需求。在ASXL2缺失时，MCF7细胞的增殖潜能和异种移植小鼠的肿瘤大小减小。结合我们在ERα阳性患者中发现的ASXL2高表达情况，我们提出ASXL2可能是乳腺癌中的一种新型预后标志物。
