YAP modulates TGF-\u03b21-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor

Yi Liu,Weiwei Shi,Kai He,Ying Hu,Xiaojie Guo,Jianguo Song,Jingsong Li,Dongmei Wang

doi:10.1038/srep45523

Abstract

YAP is a transcriptional co-regulator that plays important roles in various patho-physiological processes, including the survival and death of cells. However, the effect of YAP on apoptosis and EMT, simultaneously mediated by TGF-β1, is not known. In this study, we demonstrate that YAP can modulate cell fate of apoptosis versus EMT by acting as a surviving factor. Overexpression of YAP in mouse mammary epithelial (NMuMG) cells suppressed TGF-β1-induced apoptosis, which shifted the cellular response predominantly toward EMT. In contrast, knockdown of YAP induced spontaneous apoptosis and enhanced TGF-β1-induced apoptosis, leading to a sharp decrease in the proportion of surviving cells that underwent EMT. These data suggest that YAP is an essential factor for modulating cellular responses to TGF-β1. Further investigation showed that YAP could regulate the expression level and activation of EGFR. Knockdown or inhibition of EGFR abolished the suppressive effect of YAP on apoptosis, whereas activation of EGFR by EGF significantly reduced apoptosis caused by the knockdown of YAP. The results indicate that EGFR and its activation are critical for YAP-mediated suppression of TGF-β1-induced apoptosis. This study provides a new understanding of the regulatory mechanism underlying the determination of cell fate in response to TGF-β1-mediated simultaneous apoptosis and EMT.

Highlights

Apoptosis is widely known as a basic biological event
These results indicate that upregulation of YAP is associated with TGF-β1 -induced cell apoptosis and EMT
We showed that simultaneous apoptosis and EMT in NMuMG cells could be strongly induced by TGF-β1 treatment

Summary

Introduction

Apoptosis is widely known as a basic biological event It is a strictly programmed process for removing superfluous, aged, or damaged cells. It has been shown previously that TGF-β1-induced apoptosis and EMT were cell cycle dependent events[14]. TGF-β1 can induce both apoptosis and EMT in certain non-cancer cells, most types of cancer cells of epithelial origin escaped the apoptotic induction effect of TGF-β1. Because of the high heterogeneity of cancer cells, whether TGF-β1 is able to induce EMT in a type of cancer cell depends on the cellular context and the cell plasticity. In the absence of activated Hippo, YAP translocates into cell nucleus and promotes downstream transcription networks by interacting with the TEAD family of transcription factors[24,25]

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Conclusion