Regulation of TEAD Transcription Factors in Cancer Biology

Abstract

Transcriptional enhanced associate domain (TEAD) transcription factors play important roles during development, cell proliferation, regeneration, and tissue homeostasis. TEAD integrates with and coordinates various signal transduction pathways including Hippo, Wnt, transforming growth factor beta (TGFβ), and epidermal growth factor receptor (EGFR) pathways. TEAD deregulation affects well-established cancer genes such as KRAS, BRAF, LKB1, NF2, and MYC, and its transcriptional output plays an important role in tumor progression, metastasis, cancer metabolism, immunity, and drug resistance. To date, TEADs have been recognized to be key transcription factors of the Hippo pathway. Therefore, most studies are focused on the Hippo kinases and YAP/TAZ, whereas the Hippo-dependent and Hippo-independent regulators and regulations governing TEAD only emerged recently. Deregulation of the TEAD transcriptional output plays important roles in tumor progression and serves as a prognostic biomarker due to high correlation with clinicopathological parameters in human malignancies. In addition, discovering the molecular mechanisms of TEAD, such as post-translational modifications and nucleocytoplasmic shuttling, represents an important means of modulating TEAD transcriptional activity. Collectively, this review highlights the role of TEAD in multistep-tumorigenesis by interacting with upstream oncogenic signaling pathways and controlling downstream target genes, which provides unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics.

Keywords: Hippo pathway; TEAD; cancer; stem cell.

Figure 1

Domain architecture of human TEADs. The N-terminal DNA binding domain (DNA-BD) and C-terminal YAP/TAZ binding domain (YAP/TAZ-BD) of TEAD1-4 harbor high similarity across four different paralogs. The percent (%) represents the identity for each domain of TEADs compared to that of TEAD1 [50]. TEAD post-translation modifications include palmitoylation and PKA-, PKC-mediated phosphorylation that occur in the YAP/TAZ-BD and DNA-BD, respectively. Palmitoylation is required for proper TEAD functions. TEAD cytoplasmic translocation occurs through protein-protein interaction with p38 MAPK that binds the p38-binding motif within the DNA-BD of all TEADs.

Figure 2

The regulatory mechanisms of TEAD in cancer biology. (a) Upstream signaling and downstream transcriptional outputs of TEAD. Various oncogenic signal transduction pathways, such as EGFR signaling, TGFβ signaling, Wnt signaling, GPCR signaling, and cancer genes (*), such as KRAS, BRAF, LKB1, APC, GNAQ/11 regulate TEAD activity through multiple signaling mechanisms. The TEAD transcriptional outputs have critical functions in tumorigenesis, stem cell maintenance, cancer immunology, metabolism as well as formation of signaling feedback loops. (b) Role of TEAD in multiple stages of tumorigenesis. TEAD activation via various oncogenic pathways play critical roles in cancer biology including EMT, metastasis, drug resistance, and cancer stem cells.