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

Mengxue Yu,Rui Yang,Xuelian Li,Yaozhen Hong,Lijia Zhang,Haihai Liang,Hongli Shan,Yingzhun Chen,Longtao Huangfu,Xiaoguang Zhao,Nan Zheng,Lifang Lv

doi:10.1038/s41419-018-0515-z

Mengxue Yu, Rui Yang + Show 10 more

Open Access

https://doi.org/10.1038/s41419-018-0515-z

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Abstract

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.

Highlights

Lung cancer is the leading cause of cancer-associated death around the world[1], and approximately 80% of cases are histopathologically classified as non-small cell lung cancer (NSCLC)[2]
We show that TEAD-mediated Yes-associated protein 1 (YAP1) promotes the transcription of Slug to induce NSCLC migration and invasion
In vivo and in vitro assays confirmed that increased expression levels of YAP1 promoted cell proliferation, migration, and invasion, whereas silencing YAP1 significantly inhibited migration, invasion, and cell growth, suggesting that YAP1 is a key regulator of cell migration, invasion, and tumorigenesis in NSCLC progression

Summary

Introduction

Lung cancer is the leading cause of cancer-associated death around the world[1], and approximately 80% of cases are histopathologically classified as non-small cell lung cancer (NSCLC)[2]. Due to the early metastasis of NSCLC, the five-year survival rate of patients is lower than 15%. There has been progress in uncovering the mechanisms of lung tumorigenesis, our understanding of the molecular mechanisms of NSCLC metastasis remains limited, especially the origin of metastatic traits. The transforming growth factor beta (TGF-β) signaling pathway has been shown to be a major inducer of EMT, promoting breast cancer metastasis[7,8]. In addition to TGF-β, several other tyrosine kinase receptors, including insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF), Official journal of the Cell Death Differentiation Association

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