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Aims: Transcriptional enhanced associate domain (TEAD) transcription factor family, a very important family in the hippo signaling pathway, has been found to play oncogenic functions in the occurrence of various malignant tumors. However, the expression of TEADs in pan-cancer and the important role of TEAD4 in clear cell renal cell carcinoma (ccRCC) have not been analyzed. Herein, we aim to evaluate the expression of TEADs in pan-cancer, and focus on analyzing the role of TEAD4 in the progression of ccRCC., Main Methods: Data from the Cancer Genome Atlas (TCGA) was used to analyze the expression of TEADs in pan-cancer and its clinical correlation. TEAD4 expression in ccRCC tissues, biological functions in vitro and in vivo were analyzed by immunohistochemistry (IHC), western blotting, RNAi and Xenograft assay. Mircode, BioGRID and g: Profiler website were used to build a ceRNA network and downstream pathway prediction., Key Findings: TEAD1, TEAD2, TEAD3 and TEAD4 were highly expressed in 3, 6, 5, and 12 types of cancer tissues, respectively, indicating that TEAD4 is most closely related to tumor progression. Among the cancers with high TEAD4 expression, the expression of TEAD4 has the greatest correlation with the poor prognosis of ccRCC. We also found the malignant phenotypes of ccRCC cells in vitro and vivo have been significantly suppressed by silencing TEAD4., Significance: TEADs, especially TEAD4, were overexpressed in many human tumors. This study is the first to show that TEAD4 acts as an oncogene in ccRCC and may be an important factor in progress of ccRCC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Lung adenocarcinoma (LUAD) is a deadly disease with a hallmark of aberrant metabolism. TEA domain 4 (TEAD4) is involved in the progression of several forms of cancer including LUAD. However, the role of TEAD4 in LUAD glucose metabolism is rarely reported as well as its potential mechanisms. Pyruvate kinase isozymes M2 (PKM2), the key regulatory enzymes in glycolysis, was predicted to be a target for TEAD4 by bioinformatics analysis. Thus, we aimed to explore whether TEAD4/PKM2 axis was related to LUAD glucose metabolism and malignant phenotype. The expression level of TEAD4 and PKM2 was measured by quantitative real-time PCR and Western blot. Luciferase reporter assay were employed to verify the effect of TEAD4 on PKM2 promoter as well as TEAD4/PKM2 axis on reporter activity of hypoxia inducible factor-1α (HIF-1α). Glycolysis was investigated according to glucose consumption, lactate production and the extracellular acidification rate. The present study indicated that TEAD4 and PKM2 were upregulated in LUAD and closely related to prognosis. Mechanistic investigations identified that TEAD4 played a key role as a transcription factor and promoted PKM2 transcription and expression, which further altered the reporter activity of HIF-1α and upregulated HIF-1α-targeted glycolytic genes glucose transporter-1 and hexokinase II. Functional assays revealed that TEAD4 and PKM2 affected glycolytic and 2-DG blocked the positive function of TEAD4 and PKM2 on glycolytic. Besides, TEAD4/PKM2 axis affects LUAD cell viability, apoptosis, migration, and invasion. Together, these data provided evidence that both TEAD4 and PKM2 were poor prognosticator. Targeting TEAD4/PKM2 axis might be an effective therapeutic strategy for LUAD., (© 2021 International Federation for Cell Biology.)