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

Abstract
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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.

Data availability

All sequencing data were deposited on National Cancer for Biotechnology Information Gene Expression Omnibus (GEO). GSE166943 is the accession number for all the data, with GSE166941 being the subset for the ChIP-seq data and GSE166942 for the RNA-seq data.

The following data sets were generated

1. He L
2. Pratt H
3. Wei F
4. Gao M
5. Weng Z
6. Struhl K
(2021) YAP and TAZ are co-activators of AP-1 proteins and STAT3 during breast cellular transformation
NCBI Gene Expression Omnibus GSE166943.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE166943

The following previously published data sets were used

1. Fleming JD
2. Ji Z
3. Struhl K
(2018) Regulatory network controlling tumor-promoting inflammation in human cancers (ChIP-seq)
NCBI Gene Expression Omnibus GSE115597.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115597
1. He L
2. Ji Z
3. Struhl K
(2018) Regulatory network controlling tumor-promoting inflammation in human cancers (RNA-seq)
NCBI Gene Expression Omnibus GSE115598.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115598
1. Ji Z
2. He L
3. Rotem A
4. Janzer A
5. Cheng CS
6. Regev A
7. Struhl K
(2017) Genome-scale identification of transcription factors that mediate an inflammatory network during breast cellular transformation
NCBI Gene Expression Omnibus GSE100259.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE100259
1. Meuleman W et al
(2017) Index and biological spectrum of human DNase I hypersensitive sites
ENCODE Project ENCSR752EPH.

https://www.encodeproject.org/experiments/ENCSR752EPH/

Article and author information

Author details

Lizhi He

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-8571-3656
Henry Pratt

Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.
Mingshi Gao

Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-7524-892X
Fengxiang Wei

Genetics Laboratory, Shenzhen Longgang District Maternity and Child Healthcare Hospital, Shenzhen, China

Competing interests
No competing interests declared.
Zhiping Weng

Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3032-7966
Kevin Struhl

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States

For correspondence
kevin@hms.harvard.edu

Competing interests
Kevin Struhl, Senior editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0002-4181-7856

Funding

National Cancer Institute (GM 107486)

Kevin Struhl

National Institutes of Health (HG009486)

Zhiping Weng

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.