Tead and AP1 Coordinate Transcription and Motility

The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1–3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells. [Display omitted] •Tead and AP1 coordinate downstream transcription in diverse cancer cells•JNK-independent Tead-AP1 interaction engages SRC1–3 co-activators•Tead and AP1 regulate the activity of Dock-Rac/CDC42 module•Tead-AP1 cooperation controls migration and invasion through a core set of target genes Tead and AP1 are two families of transcription factors involved in tumorigenesis. Here, Liu et al. show Tead-AP1 co-occupancy on active enhancer or promoter regions in diverse cancer cells. This Tead-AP1 cooperation engages SRC1–3 co-activators and drives a core set of downstream target genes to coordinate cancer cell migration and invasion.