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)

  • We described an epigenetic switch that transforms breast cells via 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)

  • YAP and TAZ are important for STAT3 and AP-1 activity during breast epithelial cell transformation

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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 translocate into nucleus and act as transcriptional co-activators, most notably by interacting with the TEAD family of DNA-. Deregulation of YAP/TAZ activity is frequently observed in various human cancers, contributing to cancer initiation, progression, and metastasis (Johnson and Halder, 2014; Yu et al, 2015; Zanconato et al, 2016). 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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