生物
入侵足纲
基因敲除
癌症研究
三阴性乳腺癌
异位表达
细胞生物学
磷酸化
细胞迁移
河马信号通路
乳腺癌
细胞
细胞生长
癌细胞
上皮-间质转换
转移
癌症
焦点粘着
肌动蛋白细胞骨架
雅普1
细胞培养
肿瘤微环境
波形蛋白
作者
Ke Jiang,Peng Liu,Huizhe Xu,Dapeng Liang,Kun Fang,Sha Du,Wei Cheng,Leiguang Ye,Tong Liu,Xiaohong Zhang,Peng Gong,Shujuan Shao,Yifei Wang,Songshu Meng
出处
期刊:Oncogene
[Springer Nature]
日期:2020-06-10
卷期号:39 (27): 5015-5030
被引量:10
标识
DOI:10.1038/s41388-020-1356-7
摘要
Triple-negative breast cancer (TNBC) is extremely aggressive and lacks effective therapy. SAM and SH3 domain containing1 (SASH1) has been implicated in TNBC as a candidate tumor suppressor; however, the mechanisms of action of SASH1 in TNBC remain underexplored. Here, we show that SASH1 was significantly downregulated in TNBC patients samples compared with other subtypes of breast cancer. Ectopic SASH1 expression inhibited, while depletion of SASH1 enhanced, the invasive phenotype of TNBC cells, accompanied by deregulated expression of MMP2 and MMP9. The functional effects of SASH1 depletion were confirmed in the chicken chorioallantoic membrane and mouse xenograft models. Mechanistically, SASH1 knockdown downregulated the phosphorylation levels of the Hippo kinase LATS1 and its effector YAP (Yes associated protein), thereby upregulating YAP accumulation together with its downstream target CYR61. Consistently, forced SASH1 expression exhibited opposite effects. Pharmacological inhibition of YAP or knockdown of YAP reversed the enhanced cell invasion of TNBC cells following SASH1 depletion. Furthermore, SASH1-induced YAP signaling was LATS1-dependent, which in reverse enhanced phosphorylation of SASH1. The SASH1 S407A mutant (phosphorylation deficient) failed to rescue the altered YAP signaling by SASH1 knockdown. Notably, SASH1 depletion upregulated ARHGAP42 levels via YAP-TEAD and the YAP-ARHGAP42-actin axis contributed to SASH1-regulated TNBC cell invasion. Therefore, our findings uncover a new mechanism for the tumor-suppressive activity of SASH1 in TNBC, which may serve as a novel target for therapeutic intervention.
科研通智能强力驱动
Strongly Powered by AbleSci AI