Common and Unique Transcription Signatures of YAP and TAZ in Gastric Cancer Cells

Yaelim Lee,Boon Chuan Low,Megan Finch-Edmondson,Hamizah Cognart,Haiwei Song,Bowen Zhu,Marius Sudol

doi:10.3390/cancers12123667

Abstract

Simple SummaryYAP and TAZ are cancer-causing genes that encode proteins with similar, but not identical functions. YAP and TAZ function in diverse biological processes including cell proliferation and organ size control. Because of the high similarity in functions between YAP and TAZ, they have often been described as one entity: YAP/TAZ. However, new lines of evidence started to suggest that YAP and TAZ have unique functions as well. To understand the YAP- and TAZ-specific functions, we identified genes that are regulated solely by YAP or by TAZ. Our study revealed that YAP plays a distinct role in cell-substrate junctions, which are critical for tumour cell growth, migration, and metastasis, and both YAP and TAZ are involved in regulating blood platelets and lipid metabolism in gastric cancer cells.YAP and its paralog TAZ are the nuclear effectors of the Hippo tumour-suppressor pathway, and function as transcriptional co-activators to control gene expression in response to mechanical cues. To identify both common and unique transcriptional targets of YAP and TAZ in gastric cancer cells, we carried out RNA-sequencing analysis of overexpressed YAP or TAZ in the corresponding paralogous gene-knockouts (KOs), TAZ KO or YAP KO, respectively. Gene Ontology (GO) analysis of the YAP/TAZ-transcriptional targets revealed activation of genes involved in platelet biology and lipoprotein particle formation as targets that are common for both YAP and TAZ. However, the GO terms for cell-substrate junction were a unique function of YAP. Further, we found that YAP was indispensable for the gastric cancer cells to re-establish cell-substrate junctions on a rigid surface following prolonged culture on a soft substrate. Collectively, our study not only identifies common and unique transcriptional signatures of YAP and TAZ in gastric cancer cells but also reveals a dominant role for YAP over TAZ in the control of cell-substrate adhesion.

Highlights

YAP and its paralogous protein, TAZ, are nuclear effectors of the Hippo signalling pathway that controls organ size by regulating the balance between cell proliferation and apoptosis [1].When deregulated, amplified, or fused to genes encoding transcription factors, YAP and TAZ can act as potent oncogenes [2]
We identified common YAP/TAZ transcription targets in gastric cancer cells, which function in platelet biology and lipoprotein particles assembly
To interrogate the common and distinct transcripts regulated by YAP and TAZ at the genome-wide level, we used a gastric cancer cell line, MKN28 [11]

Summary

Introduction

YAP and its paralogous protein, TAZ, are nuclear effectors of the Hippo signalling pathway that controls organ size by regulating the balance between cell proliferation and apoptosis [1].When deregulated, amplified, or fused to genes encoding transcription factors, YAP and TAZ can act as potent oncogenes [2]. YAP/TAZ are frequently referred to as mechano-responders because of their ability to translocate into the nucleus to activate the transcriptional program in response to various mechanical cues, such as stiffness of substrate, cell stretching, fluid friction stress, or changes in the size of the adhesive area [7]. These biophysical signals are often altered in the tumour microenvironment, which closely interacts with cancer cells, leading to abnormal cellular responses such as proliferation and invasion [8,9]. It is still not clear if YAP and TAZ play redundant or specific roles in mechanotransduction

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