YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD.
YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD.
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YAP1 通过转录辅助因子 TEAD 促进 Slug 转录，从而促进 NSCLC 侵袭和迁移
DOI：
10.1038/s41419-018-0515-z
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Shan H
中科院分区：
文献类型：
--
作者：
Yu M;Chen Y;Li X;Yang R;Zhang L;Huangfu L;Zheng N;Zhao X;Lv L;Hong Y;Liang H;Shan H
YAP 1与多种肿瘤的发生发展有关，但YAP 1在非小细胞肺癌（NSCLC）中失调的机制尚不清楚。通过进行免疫组织化学（IHC）检测，我们发现与邻近组织相比，YAP 1在NSCLC中显著上调;因此，我们试图阐明YAP 1的上调是否有助于NSCLC进展。MTT和transwell实验结果显示，YAP 1过表达可促进A549和H460细胞的增殖、迁移和侵袭，并促进上皮间质转化（EMT）相关标志物的表达。然而，YAP 1敲低可减轻TGF-β1诱导的EMT以及NSCLC的增殖、迁移和侵袭。Western blotting结果显示，YAP 1/TEAD共转录复合物被YAPS 94 A（一种缺失TEAD结合位点的YAP 1突变体）破坏，而Vetriporfin（一种YAP 1的小分子抑制剂）抑制A549和H460细胞的转移和EMT相关标志物的表达，表明TEAD介导了YAP 1诱导的NSCLC侵袭性。此外，序列分析和ChIP和荧光素酶测定证实，YAP 1通过结合TEAD转录激活Slug表达。重要的是，沉默YAP 1抑制A549细胞肿瘤发生和EMT，并下调体内Slug表达。总的来说，我们的研究结果表明，YAP 1是NSCLC转移的驱动因素，因为YAP 1通过诱导Slug转录促进EMT程序。
Yes-associated protein 1 (YAP1) contributes to the development of multiple tumors, but the mechanism underlying YAP1 deregulation in non-small cell lung cancer (NSCLC) remains unclear. By performing immunohistochemistry (IHC) assays, we found that YAP1 was significantly upregulated in NSCLC compared with adjacent tissues; therefore, we sought to elucidate whether the upregulation of YAP1 contributes to NSCLC progression. MTT and transwell assays showed that YAP1 overexpression promoted proliferation, migration, and invasion in the NSCLC cell lines A549 and H460; YAP1 overexpression also promoted the significant differential expression of epithelial-mesenchymal transition (EMT)-related markers. Nevertheless, YAP1 knockdown alleviated TGF-β1-induced EMT and proliferation, migration, and invasion in NSCLC. Furthermore, western blotting showed that the co-transcription complex YAP1/TEAD was impaired by YAPS94A (a YAP1 mutant without the TEAD binding site), and verteporfin (a small molecular inhibitor of YAP1) inhibited A549 and H460 cell metastasis and EMT-related markers expression, indicating that TEAD mediated the NSCLC aggressiveness induced by YAP1. Moreover, sequence analysis and ChIP and luciferase assays confirmed that YAP1 transcriptionally activated Slug expression by binding to TEAD. Importantly, silencing YAP1 inhibited A549 cell tumorigenesis and EMT and downregulated Slug expression in vivo. Overall, our findings revealed that YAP1 is a driver of NSCLC metastasis because YAP1 promoted the EMT program by inducing Slug transcription.
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