YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation.

Lizhi He,Mingshi Gao,Henry Pratt,Zhiping Weng,Kevin Struhl,Fengxiang Wei

doi:10.7554/elife.67312

Lizhi He, Mingshi Gao + Show 4 more

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https://doi.org/10.7554/elife.67312

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Abstract

The YAP and TAZ paralogs are transcriptional co-activators recruited to target sites by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB (a member of the AP-1 family) and STAT3, key transcription factors that mediate an epigenetic switch linking inflammation to cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain important for transformation, and they stimulate transcriptional activation by AP-1 proteins. JUNB, STAT3, and TEAD co-localize at virtually all YAP/TAZ target sites, yet many target sites only contain individual AP-1, TEAD, or STAT3 motifs. This observation and differences in relative crosslinking efficiencies of JUNB, TEAD, and STAT3 at YAP/TAZ target sites suggest that YAP/TAZ is recruited by different forms of an AP-1/STAT3/TEAD complex depending on the recruiting motif. The different classes of YAP/TAZ target sites are associated with largely non-overlapping genes with distinct functions. A small minority of target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes from shared YAP/TAZ target sites. Genes containing either the AP-1 or TEAD class of YAP/TAZ sites are associated with poor survival of breast cancer patients with the triple-negative form of the disease.

Highlights

The Hippo signal transduction pathway plays critical roles in development, homeostasis, and tumor progression (Piccolo et al, 2014; Varelas, 2014; Yu et al, 2015; Totaro et al, 2018; Moya and Halder, 2019)
Given the importance of YAP and TAZ in many types of human cancer, we examined their roles in breast cellular transformation by using CRISPR to knock out these genes in the context of our Src-inducible model (MCF-10A cells containing ER-Src, a fusion of the tamoxifen-inducible ligand binding domain of estrogen receptor and the v-Src oncoprotein)
YAP and TAZ are important for transformation in ER-Src cells, which is mediated by an epigenetic switch involving an inflammatory regulatory network controlled by the joint action of NF-κB, STAT3, and AP-1 transcription factors (Iliopoulos et al, 2009; Iliopoulos et al, 2010; Ji et al, 2018; Ji et al, 2019)

Summary

Introduction

The Hippo signal transduction pathway plays critical roles in development, homeostasis, and tumor progression (Piccolo et al, 2014; Varelas, 2014; Yu et al, 2015; Totaro et al, 2018; Moya and Halder, 2019). Internal and external signals relayed through the Hippo pathway converge on YAP and TAZ, paralogous proteins with 63% sequence similarity that are the major effectors of this pathway (Piccolo et al, 2014; Totaro et al., 2018; Ma et al, 2019). YAP/TAZ activation is linked to chemo-resistance in cancer therapy (Johnson and Halder, 2014; Yu et al, 2015; Zanconato et al, 2016). The transcriptional mechanisms and regulatory circuits mediated by YAP/TAZ in cancers beyond those associated with TEAD proteins, are not well understood

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