Wang Chunyan, Nie Zhi, Zhou Zhongmei, Zhang Hailin, Liu Rong, Wu Jing, Qin Junying, Ma Yun, Chen Liang, Li Shumo, Chen Wenlin, Li Fubing, Shi Peiguo, Wu Yingying, Shen Jian, Chen Ceshi
Key Laboratory of Animal Models and Human Disease Mechanisms of The Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
University of The Chinese Academy of Sciences, Beijing, China.
Oncotarget. 2015 Jul 10;6(19):17685-97. doi: 10.18632/oncotarget.3779.
Growing evidence suggests that YAP/TAZ are mediators of the Hippo pathway and promote breast cancer. However, the roles of YAP/TAZ transcription factor partners TEADs in breast cancer remain unclear. Here we found that TEAD4 was expressed in breast cancer cell lines, especially in triple negative breast cancers (TNBC) cell lines. TEAD4 binds to KLF5. Knockdown of either TEAD4 or KLF5 in HCC1937 and HCC1806 cells induced the expression of CDK inhibitor p27. Depletion of either TEAD4 or KLF5 activated the p27 gene promoter and increased the p27 mRNA levels. Depletion of p27 partially prevents growth inhibition caused by TEAD4 and KLF5 knockdown. TEAD4 overexpression stimulated proliferation in vitro and tumor growth in mice, while stable knockdown of TEAD4 inhibited proliferation in vitro and tumor growth in mice. Thus TEAD4 and KLF5, in collaboration, promoted TNBC cell proliferation and tumor growth in part by inhibiting p27 gene transcription. TEAD4 is a potential target and biomarker for the development of novel therapeutics for breast cancer.
越来越多的证据表明，YAP/TAZ是Hippo信号通路的介质，并促进乳腺癌的发生。然而，YAP/TAZ转录因子伴侣TEADs在乳腺癌中的作用仍不清楚。在这里，我们发现TEAD4在乳腺癌细胞系中表达，尤其是在三阴性乳腺癌（TNBC）细胞系中。TEAD4与KLF5结合。在HCC1937和HCC1806细胞中敲低TEAD4或KLF5会诱导细胞周期蛋白依赖性激酶（CDK）抑制剂p27的表达。敲除TEAD4或KLF5会激活p27基因启动子并增加p27 mRNA水平。敲除p27可部分阻止由TEAD4和KLF5敲低引起的生长抑制。过表达TEAD4会刺激体外细胞增殖和小鼠体内肿瘤生长，而稳定敲低TEAD4则会抑制体外细胞增殖和小鼠体内肿瘤生长。因此，TEAD4和KLF5协同作用，部分通过抑制p27基因转录来促进TNBC细胞增殖和肿瘤生长。TEAD4是开发新型乳腺癌治疗药物的潜在靶点和生物标志物。
