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

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.

Contribution of the Transcription Factors Sp1/Sp3 and AP-1 to Clusterin Gene Expression during Corneal Wound Healing of Tissue-Engineered Human Corneas

“…More recently, a few more studies further identified novel AP-1 co-activators. For instance, the dimeric RACO-1 protein was identified as a c-Jun coactivator, and both YAP (Yes-associated protein) and TAZ (Transcriptional activator with PDZ domain) proteins as b-Jun co-activators required for transcriptional activation by AP-1 [87,88]. As both YAP and TAZ were recently found to be key mediators of the wound healing and tissue regeneration responses to tissue damage [89], it would prove particularly interesting to determine whether both these proteins are expressed in the hTEC and if their expression is affected by wound healing in this biological model.…”

The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer

“…Similar to the intact Yki, this fragment retains the ability to be phosphorylated by Wts, suggesting that this is independent of WW binding to Wts and regulation of Yki phosphorylation [ 79 ]. The WW domain in YAP is, however, essential for its activity in order to drive proliferation in vitro and in vivo [ 79 , 80 ] and can facilitate association between YAP and a variety of transcription factors, such as ERBB4 [ 81 , 82 ], JUNB [ 83 ] and RUNX2 [ 84 ], suggesting a TEAD-independent role for YAP as a transcriptional co-activator. A total of eight isoforms of YAP have been reported [ 85 ], with two major isoform types: YAP1 and YAP2, which contain one and two WW domains respectively [ 81 ].…”

“…These pro-proliferative transcriptional programs may be driven in part by YAP/TAZ–TEAD association with the cell cycle transcription factor complex, AP-1. In a variety of cancer cell lines, YAP, TAZ and TEAD are found to colocalise with AP-1 to regulatory elements of the genome and are necessary for AP-1-mediated expression of cell cycle transcriptional programs, driving cancer cell proliferation and tumorigenesis in in vivo xenograft models [ 83 , 125 , 126 ]. Hyperactive YAP/TAZ also provides cells with a metabolic competitive advantage under nutrient-limiting conditions, in part by up-regulating glucose and high-affinity amino acid transporters [ 127–129 ].…”

“…This discovery is of particular relevance currently given the recent focus on leveraging immunotherapy to manage a wide variety of cancer types [ 262 , 263 ], with a combinatorial approach that simultaneously targets YAP/TAZ activity potentially overcoming the resistance associated with immunotherapy [ 264 , 265 ]. Noteworthily, enforced expression of constitutively activated YAP/TAZ in a range of tissue culture and cancer cells regularly induces expression of inflammatory cytokines [ 83 , 266–270 ], which directly highlights that the Hippo pathway is likely a cellular nexus that links epithelial, fibroblasts and endothelial inflammatory responses and proliferation during cancer onset and development [ 13 , 261 , 266 ].…”

MafB, WDR77, and ß-catenin interact with each other and have similar genome association profiles

“…In addition, cellular transformation depends on transcriptional co-activators that are key components of signal transduction pathways and are recruited to target sites by DNA-binding proteins. Such co-activators include the YAP and TAZ paralogues, the ultimate targets of the Hippo signaling pathway [ 6 ], and the calcium-binding cytokines S100A8 and S100A9 [ 7 ].…”