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.
Highlights
The Transcriptional enhanced associate domain (TEAD) family of transcription factors are the final nuclear effectors of the Hippo pathway, which regulate cell growth, proliferation, and tissue homeostasis via their transcriptional target genes.Since their initial discovery three decades ago, TEADs have been best studied in the context of theHippo-YAP/TAZ signaling pathway and tumorigenesis
Wnt and Hippo pathways converge on TEAD via destruction complex-dependent and -independent mechanisms, which have been studied in the context of tumorigenesis, stem cell biology, and development
The results indicated that NSAIDs, such as flufenamic acid (FA) and niflumic acid (NA), were small-molecular inhibitors that bound the central TEAD hydrophobic pocket at its palmitoylation site [103]
Summary
The TEAD family of transcription factors are the final nuclear effectors of the Hippo pathway, which regulate cell growth, proliferation, and tissue homeostasis via their transcriptional target genes. Since their initial discovery three decades ago, TEADs have been best studied in the context of the. Studies on TEAD activity are limited to serving as the functional readout of the Hippo-YAP/TAZ pathway. Recent evidence suggests that nucleocytoplasmic shuttling, post-translational modifications, and crosstalk between oncogenic signaling pathways are important determinants of TEAD activity both in vitro and in vivo. The current review underscores and reinterprets the oncogenic role of TEADs in tumorigenesis in past reports from a TEAD point of view in order to provide unprecedented insight and rationale into developing TEAD-targeted anticancer therapeutics
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