Tead and AP1 Coordinate Transcription and Motility

Abstract

SUMMARY 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 coactivators 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.

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

“…In a mouse heart regeneration study, loss of salvador (sav) leads to transcriptional activation of several actin-related genes (Morikawa et al, 2015), suggesting that Yki may regulate actin regulators at the transcriptional level. Indeed, activation of migration-related genes by YAP/TEAD factors has also been observed in metastatic contexts (Liu et al, 2016). If this mechanism is conserved during larval WC, the specific Yki/Sd target genes that might be related to wound-induced migration have yet to be elucidated.…”

“…However, the JNK downstream transcriptional factors, Activation Protein-1 family genes (AP-1), D-Jun and D-Fos, are required for larval WC (Lesch et al, 2010). Jun physically interacts with TEAD4 in colon cancer cells (Liu et al, 2016) and could potentially interact directly with Yki to regulate transcription as observed in cancer cells (Verfaillie et al, 2015; Zanconato et al, 2015). Some of the transcriptional targets that shared AP-1 and TEAD binding sites include actin regulators (Liu et al, 2016).…”

“…Jun physically interacts with TEAD4 in colon cancer cells (Liu et al, 2016) and could potentially interact directly with Yki to regulate transcription as observed in cancer cells (Verfaillie et al, 2015; Zanconato et al, 2015). Some of the transcriptional targets that shared AP-1 and TEAD binding sites include actin regulators (Liu et al, 2016). The Drosophila ortholog of at least one of these target genes, DOCK, is a known larval WC gene (Lesch et al, 2010).…”

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

“…6D), and expression of E6 in NIKS did not increase the CTGF mRNA levels (data not shown), suggesting different requirements for coactivators between the two promoters. We speculate that YAP/TAZ are the limiting factors for TEAD-mediated CTGF transactivation, while coactivators other than YAP/TAZ, such as Vgll (35,36) and SRC3 (37,38), might be involved in A3B transactivation by TEAD. In support of this scenario, YAP and constitutively active YAP (5SA) only modestly activated the A3B promoter (Fig.…”

“…A genome-wide ChIP sequencing study revealed that TEAD4 binds to its own promoter and that YAP is required for TEAD4 expression (38), which suggests a positive-feedback mechanism for TEAD4 expression through TEAD4/YAP. In that study, TEAD4 binding to the TEAD1 promoter was also demonstrated (38), suggesting that TEAD1 expression can be upregulated by TEAD4/ YAP. In agreement with these findings, we found that overexpression of YAP was associated with increased TEAD1/4 levels in NIKS-E6 (Fig.…”