Transcriptional enhanced associate domain (TEAD) transcription factor family is essential during development. The family comprises of a TEA domain to bind to DNA molecules and a transcriptional activation domain to bind to transcriptional cofactors. TEAD proteins help carry on downstream signalling. TEAD is involved in both physiological growth and tumour formation. The function of TEAD in cancer is:
| TEAD stimulates progression-associated genes |
TEAD stimulates cancer development by turning on a cascade of cancer progression-associated genes, including CTGF, Cyr61, Myc and Gli2 |
| Function in various malignancies |
It's been reported that TEAD and its cofactors are implicated in numerous malignancies, including liver cancer, ovarian cancer, breast cancer and prostate cancer, and promote tumor transformation into malignant cells. |
| Prognostic biomarker |
Because the high expression of TEAD in gastric cancer, breast cancer, ovarian and prostate cancer is well correlated with pathology, it is a prognostic biomarker that can be used to assess the prognosis of patients with tumours. |
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Transcriptional Enhanced Associate Domain Transcription Factor Family
TEADs can be found in almost all tissues in the human body, and they belong to the family of TEAD1 (TEF-1/NTEF), TEAD2 (TEF-4/ETF), TEAD3 (TEF-5/ETFR-1), and TEAD4 (TEF-3/ETFR-2/FR-19). TEADs share similar domain structures too, and there's a highly conserved 68-amino acid TEA/ATTS DNA binding domain at the N-terminus of TEAD binding to the MCAT element (5′-CATTCCA/T-3′) of the GT-IIC motif (5′-ACATTCCAC-3′) first identified as the simian virus 40 (SV40) enhancer. On the basis of these sequences, we have a TEAD luciferase reporter gene 8xGTIIC-luciferase plasmid with eight GT-IIC motifs that is widely used to quantify YAP/TAZ and TEAD activities.
Fig. 1 TEAD family and structure (Huh, H., et al. 2019).
TEADs attach most commonly to DNA because most TEADs are present in chromatin fractions. The C-terminus, the locus of TEAD activity, is responsible for recruiting transcriptional coactivators YAP/TAZ [all TEADs possess the same transcription activation domain], corepressors VGLL1-4 and chromatin remodelers NuRD and Mediator. TEAD-driven transcriptional targets include genes known to function in cell growth, proliferation and tissue homeostasis. Such signalling inputs, protein-protein interactions and target genes further extend TEADs' functional reach to direct modulation of Wnt, TGF, RTK, mTOR and Hippo signalling in tumorigenesis, cancer immunity, stem cell pluripotency, metabolism and development.
Molecular Mechanisms Controlling Transcriptional Enhanced Associate Domain Activity
TEAD Control Through Subcellular Localization
Nuclear loss of TEAD damages nuclear buildup of YAP/TAZ. In TEAD 1/2/4 KO cells, for instance, LPA-induced YAP/TAZ didn't get loaded into the nucleus even after full dephosphorylation. Thus, cytoplasmic translocation stimuli for TEAD block YAP/TAZ activation. The stress- and p38-driven TEAD cytoplasmic retention system is intact in different cancer cells. More importantly, YAP-driven cancer cells (GNAQ/11 mutant uveal melanoma cells, Hippo mutant mesothelioma cells) are more sensitive to TEAD cytoplasmic translocation than YAP-free cancer cells. This results indicate that signalling and/or chemical compounds that drive TEAD subcellular localisation could be the controlling biological drivers of the Hippo-YAP/TAZ pathway.
TEAD Regulation by Post-translational Modifications
Protein kinases A (PKA) and C (PKC) phosphorylate TEAD and inhibit TEAD by breaking its DNA binding. The first sign that the hydrophobic pocket might be a therapeutic candidate was a high-throughput screen that looked for ligands that stabilize TEAD-YBD. It was revealed that NSAIDs like flufenamic acid (FA) and niflumic acid (NA) are small molecule inhibitors that stick to the central TEAD hydrophobic pocket at its palmitoylation site. While these drugs must be regulated to optimize their affinity to TEAD, treatment with FA and NA inhibited TEAD transcription and TEAD-induced cell migration and proliferation but not the TEAD-YAP interaction.
The Role of Transcriptional Enhanced Associate Domain in Cancer Biology
TEAD Expression in Human Cancer
There is no shortage of studies showing the significance of TEAD in the pathogenesis of human cancer. TEAD-overexpression and hyperactivity have been linked to different types of cancers. While TEAD is deregulated in certain breast, kidney, or bladder tumors, TEAD levels that are elevated are associated with poor clinical prognosis and may be used as a prognostic indicator for prostate cancer, colorectal cancer, gastric cancer, breast cancer, germ cell tumors, head and neck squamous cell carcinoma, renal cell carcinoma, and medulloblastoma.
TEAD Role in EMT
TEAD has now become a major source of cancer formation, tumor development, EMT, disease progression, and drug resistance. EMT is a naturally occurring process that epithelial cancer cells phenotypically mimic. It's necessary for cancer cells because it enables cell movement, invasion, and apoptosis resistance. In this way, EMT is a determinant of the cancer stem cell type and an entry point for metastasis. TEAD is a major intermediary between EMT and metastasis in the course of cancer. This has been proven multiple times: TEAD transcriptional activity induced by YAP/TAZ activation is responsible for cell transformation via EMT. TEAD turns cell-cell contacts off, releases mesenchymal genes, and exacerbates cell migration and invasion. There is evidence that aberrant TEAD activity contributes to breast cancer and melanoma metastasis very strongly dependent on the YAP interaction domain, so it appears that the interaction between TEAD and YAP is essential for EMT and metastasis.
Role of TEAD in Metastasis
It's metastasis, the movement of cancer cells from the initial tumor to later organs, that accounts for most deaths from cancer. For cancer cells to spread, they must resist apoptosis (shedding-induced apoptosis), cross into and out of blood vessels (endovasculature and extravasation, respectively), become metastatic colonized, and become drug resistant. They are hallmarks of cancer stem cells. When cells that are cancerous and are metastatic activate TEAD, in response to a platelet signal, they activate RhoA-MYPT1-PP1-YAP. Platelet-triggered TEAD transcriptional code in shedding cancer cells causes resistance to apoptosis and encourages cell survival and invasion. TEAD target gene CTGF turns on to promote metastatic colonization in breast cancer by suppressing the leukemia inhibitory factor receptor (LIFR). RAR in colorectal cancer stimulates TEAD via the Hippo pathway and so leads to EMT, invasion, and spread. In breast cancer and melanoma cells, SRC tyrosine kinase-mediated cell-ECM adhesion signals to TEAD to increase tumor growth and spread.
Transcriptional Enhanced Associate Domain as Chemomotor of Oncogenes
Cancer-associated driver mutations disrupt downstream signaling and transcriptional patterns involved in the spread of the tumor. Regulating TEAD transcriptional output is also etiologically involved in the pathology of oncogenes and tumor suppressor genes such as NF2, BRAF, KRAS, MYC, PTEN, LKB1 and PKA (Figure 2a). This is where we will talk about molecular mechanisms of TEAD regulation during oncogene-induced tumorigenesis, drug resistance and metastatic disease.
Conclusion
The molecular machinery and activities of transcriptional enhanced associate domain (TEAD) are a member of the four-step pathway of tumor growth, EMT, drug resistance, and spread. TEAD-related oncogenic driver mutations are still unknown, but the transcriptional output of TEAD has been shown to be involved in human malignancies via crosstalk between oncogenic signaling pathways and cancer genes including the Hippo pathway, the EGFR-RAS-RAF-MEK pathway, LKB1, GNAQ/11 and MYC. Even though TEADs are now one of the most important effectors in cancer biology, most work on TEAD regulation has involved their major coactivators, YAP and TAZ. YAP/TAZ-independent regulators of TEAD function – from post-translational changes to subcellular distribution and upstream activating and inhibitory factors – have largely gone uninvestigated. With TEADs announcing the intersection for critical stages of cancer development, the next few years in defining TEAD regulation and developing therapeutic interventions represent a potentially very promising area for fundamental science and pharmacology.
References
- Huh, H., et al. Regulation of TEAD transcription factors in cancer biology. Cells. 2019, 8(6): 600.
- Lin, K., et al. Regulation of the Hippo pathway transcription factor TEAD. Trends in biochemical sciences. 2017, 42(11): 862-872.
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