YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD

摘要

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.