{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTEAD4 is a critical transcription factor and major effector of the Hippo pathway that orchestrates diverse transcriptional programs in cancer and development. Several studies demonstrate that TEAD4 forms complexes with various partners—such as AP1 factors that synergize to promote cell migration and invasion in diverse carcinomas"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", TCF4 to integrate Hippo and Wnt/β-catenin signals"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", and KLF5 to suppress inhibitors of cell cycle progression in triple‐negative breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", as well as acting as a co‐regulator on enhancers in ERα‐positive breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "—thereby modulating the expression of genes that drive epithelial‐mesenchymal transition, proliferation, invasion, and even senescence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Furthermore, epigenetic deregulation—with TEAD4 promoter hypomethylation in gastric cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "—and microRNA‐mediated control"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "further enhance its oncogenic potential."}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTEAD4 activity is finely tuned at multiple levels. Post‐translational modifications such as acylation enhance its protein stability"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "while alternative splicing produces a truncated dominant negative isoform, TEAD4-S, that counteracts YAP-driven transcription."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Hormonal signals, including glucocorticoids, promote GR-dependent TEAD4 nuclear accumulation to support breast cancer stemness, metastasis, and chemoresistance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and structural studies have detailed its interaction with YAP/TAZ"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "as well as with other cofactors such as VGLL3 in myogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In various tumor types—including colorectal"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", lung adenocarcinoma"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "20"}]}, {"type": "t", "text": ", esophageal"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", breast"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", oral squamous"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and hepatoblastoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "—TEAD4 is frequently overexpressed, displays nuclear accumulation associated with aggressive features, and regulates downstream targets such as vimentin, MAD2L1, and PKM2 that modulate metabolism and epithelial plasticity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " Moreover, genetic variants in TEAD4 have been linked to patient survival in melanoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": ", while long-range enhancer–promoter interactions regulating TEAD4 expression are crucial for trophectoderm differentiation during early embryonic development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Lastly, insights from detailed mutagenesis at the YAP:TEAD interface"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "and regulation by novel microRNAs"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "underline the complexity of TEAD4 regulation. 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