Mimoto R, Imawari Y, Hirooka S, Takeyama H, Yoshida K
Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan.
Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.
Oncogene. 2017 Mar 30;36(13):1862-1872. doi: 10.1038/onc.2016.349. Epub 2016 Oct 10.
Whereas accumulating studies have supported the cancer stem cell theory, a specific therapy targeting a cancer stem cell subpopulation has not been established. Here, we show that dual-specificity tyrosine phosphorylation-kinase 2 (DYRK2) is a novel negative regulator for formation of breast cancer stem cells. Downregulation of DYRK2 promotes cancer stem-like traits in vitro, tumourigenesis in vivo and the proportion of the cancer stem cell population in human breast cancer tissues. We found that Krupple-like factor 4 (KLF4) serves as a key mediator of DYRK2's control over the cancer stem phenotype. Reduced DYRK2 expression increases KLF4 expression, which induces cancer stem-like properties. We identified androgen receptor (AR) as a transcription factor binding to the KLF4 promoter region; this process is dependent on DYRK2 kinase activity. Our findings delineate a mechanism of cancer stem cell regulation by the DYRK2-AR-KLF4 axis in breast cancer. Targeting of this pathway may be a promising strategy against breast cancer stem cells.
尽管越来越多的研究支持癌症干细胞理论，但尚未建立针对癌症干细胞亚群的特异性疗法。在此，我们表明双特异性酪氨酸磷酸化激酶2（DYRK2）是乳腺癌干细胞形成的新型负调控因子。DYRK2的下调促进体外癌症干细胞样特性、体内肿瘤发生以及人类乳腺癌组织中癌症干细胞群体的比例。我们发现 Krupple 样因子4（KLF4）是 DYRK2 控制癌症干细胞表型的关键介质。DYRK2 表达降低会增加 KLF4 表达，从而诱导癌症干细胞样特性。我们确定雄激素受体（AR）为与 KLF4 启动子区域结合的转录因子；这一过程依赖于 DYRK2 激酶活性。我们的研究结果阐明了乳腺癌中 DYRK2-AR-KLF4 轴对癌症干细胞的调控机制。靶向该途径可能是对抗乳腺癌干细胞的一种有前景的策略。
