SASH1 suppresses triple-negative breast cancer cell invasion through YAP-ARHGAP42-actin axis
SASH1 suppresses triple-negative breast cancer cell invasion through YAP-ARHGAP42-actin axis
复制标题
SASH1通过YAP-ARHGAP42-肌动蛋白轴抑制三阴性乳腺癌细胞侵袭
DOI：
10.1038/s41388-020-1356-7
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发表时间：
2020-06-10
期刊：
影响因子：
8
通讯作者：
Meng, Songshu
中科院分区：
文献类型：
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作者：
Jiang, Ke;Liu, Peng;Meng, Songshu
三阴性乳腺癌（TNBC）具有极强的侵袭性，缺乏有效的治疗。SAM和SH 3结构域包含1（SASH 1）已被牵连在TNBC作为一个候选的肿瘤抑制剂;然而，SASH 1在TNBC中的作用机制仍有待探索。在这里，我们表明，SASH 1在TNBC患者样本中与其他乳腺癌亚型相比显著下调。异位SASH 1表达抑制，而SASH 1的消耗增强，TNBC细胞的侵袭表型，伴随着MMP 2和MMP 9的表达失调。SASH 1耗竭的功能效应在鸡绒毛尿囊膜和小鼠异种移植模型中得到证实。从机制上讲，SASH 1敲低下调了Hippo激酶LATS 1及其效应物雅普（Yes相关蛋白）的磷酸化水平，从而上调了雅普及其下游靶标CYR 61的积累。一致地，强迫SASH 1表达表现出相反的效果。雅普的药理学抑制或雅普的敲低逆转了SASH 1耗竭后TNBC细胞的增强的细胞侵袭。此外，SASH 1诱导的雅普信号是LATS 1依赖性的，这反过来增强了SASH 1的磷酸化。SASH 1 S407 A突变体（磷酸化缺陷）未能通过SASH 1敲低来挽救改变的雅普信号传导。值得注意的是，SASH 1消耗通过YAP-TEAD上调ARHGAP 42水平，YAP-ARHGAP 42-肌动蛋白轴有助于SASH 1调节的TNBC细胞侵袭。因此，我们的研究结果揭示了SASH 1在TNBC中肿瘤抑制活性的新机制，这可能成为治疗干预的新靶点。
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.