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

The YAP and TAZ paralogues, the ultimate effectors of the Hippo signaling pathway, are deregulated in many cancer types. They are transcriptional co-activators that are recruited to their target sites, primarily by TEAD proteins. Here, we show that YAP and TAZ are also recruited by JUNB and STAT3, key factors that mediate an epigenetic switch linking inflammation to breast cellular transformation. YAP and TAZ directly interact with JUNB and STAT3 via a WW domain that is important for transformation, co-occupy many target sites in vivo via the sequence motifs of AP-1 and (to a lesser extent) STAT3, and stimulate transcriptional activation by AP-1 proteins. A small minority of target sites are YAP- or TAZ-specific, and they are associated with different sequence motifs and gene classes. YAP/TAZ, JUNB, and STAT3 directly regulate a common set of target genes that overlap, but are distinct from, those regulated by YAP/TAZ and TEADs. The set of target genes regulated by YAP/TAZ, STAT3, and JUNB is associated with poor survival in breast cancer patients with the triple-negative form of the disease. Overall design: YAP/TAZ, AP-1 and STAT3 transcriptional regulation in breast cancer

YAP与TAZ这对旁系同源蛋白（paralogues），是Hippo信号通路（Hippo signaling pathway）的最终效应因子，在多种癌症类型中存在表达失调现象。二者作为转录共激活因子，主要通过TEAD蛋白（TEAD proteins）被招募至靶位点。本研究证实，YAP与TAZ还可被介导炎症与乳腺细胞转化间表观遗传开关的关键因子JUNB及STAT3所招募。YAP与TAZ通过对细胞转化至关重要的WW结构域（WW domain），直接与JUNB和STAT3发生相互作用；二者可通过AP-1序列基序（辅以少量STAT3序列基序）在体内共同结合大量靶位点，并促进AP-1蛋白介导的转录激活。仅有极少数靶位点为YAP或TAZ所特有，这些位点与不同的序列基序及基因类别相关。YAP/TAZ、JUNB与STAT3可共同调控一组重叠的靶基因，该组基因与YAP/TAZ及TEAD所调控的靶基因存在显著差异。YAP/TAZ、STAT3与JUNB所调控的这组靶基因，与三阴性乳腺癌（triple-negative breast cancer）患者的不良生存预后显著相关。整体实验设计：乳腺癌中YAP/TAZ、AP-1与STAT3的转录调控研究。