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.

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…Among typical YAP/TAZ targets are several secretory factors, including amphiregulin, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61), which are important in stromal interactions and niche formation of cancer metastasis [18][19][20][21][22].There is ample and rapidly growing literature on the mechanisms of YAP/TAZ regulation, particularly by the Hippo signaling pathway, which prohibits organ overgrowth through the regulation of cell proliferation and cell survival during normal development. Recent excellent and comprehensive reviews summarize this wealth of published information from different angles: from a protein structural perspective [23,24]; from the angle of tissue mechanics, microenvironment and cytoskeleton interactions [25][26][27]; from the aspect of DNA-binding protein partners of YAP/TAZ [28,29] and in the context of normal development [30]; specific cancers (i.e., of the breast [31], lung [32] liver [33], prostate [34], pancreas [35] and various pediatric cancers [36]) and other chronic and neurodegenerative diseases [37,38].The adaptation to microenvironments of different tissue architecture plays a particularly important role in bone cancers which tend to metastasize through the hematogenous route and home primarily to bone and lungs, which are organs of completely different stiffness, extracellular matrix composition and oxygen supply. It is therefore not unexpected that the YAP/TAZ signaling pathway is prominently involved in bone cancer pathogenesis and metastatic spread.…”

“…There is ample and rapidly growing literature on the mechanisms of YAP/TAZ regulation, particularly by the Hippo signaling pathway, which prohibits organ overgrowth through the regulation of cell proliferation and cell survival during normal development. Recent excellent and comprehensive reviews summarize this wealth of published information from different angles: from a protein structural perspective [23,24]; from the angle of tissue mechanics, microenvironment and cytoskeleton interactions [25][26][27]; from the aspect of DNA-binding protein partners of YAP/TAZ [28,29] and in the context of normal development [30]; specific cancers (i.e., of the breast [31], lung [32] liver [33], prostate [34], pancreas [35] and various pediatric cancers [36]) and other chronic and neurodegenerative diseases [37,38].…”

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

“…TEAD proteins regulate the transcription of cell proliferation, differentiation and apoptosis genes. Their activation promotes tumorigenesis and progression through the overexpression of Cyr61, Birc5, Ankrd1, vimentin and N-cadherin genes in various tumors [109][110][111][112][113].…”

“…The two isoforms show the opposite roles in cancer in vitro and in vivo, with TEAD4-FL being a tumor promoter and TEAD4-S a tumor suppressor [115]. Clinical investigation and TCGA data analysis highlighted that TEAD4-S expression is commonly reduced in human cancers and patients with elevated TEAD4-S levels show improved survival [111,115]. In particular, in lung cancer cells, which have lower TEAD4-S level compared with normal cells, TEAD4-FL activates transcription of N-cadherin and vimentin genes inducing EMT of tumor cells, while TEAD4-S suppresses EMT markers [115].…”

ADrosophilamodel of oral peptide therapeutics for adult Intestinal Stem Cell tumors

“…The proto-oncogene YAP (Yes-associated protein), a transcription co-factor of the Hippo pathway, has been linked to many cancers (see review (13)). YAP interacts with DNA-binding TEAD proteins (transcriptional enhanced associate domain, TEAD1-4) to regulate expression of its transcriptional targets, and an increase in levels of TEAD proteins has been observed in a wide range of human cancers (14). YAP binds to TEAD via an unusually large interface, the Ω-loop (12, 15) that lacks a defined binding pocket, making it an unlikely target of inhibition by small molecules.…”