• Epithelial-mesenchymal transition (EMT)
• Glycolysis
• Histone lactylation
• NLRP3 inflammasome
• SIX1
• Silica

• Humans
• Epithelial-Mesenchymal Transition/drug effects
• Up-Regulation/drug effects
• Silicon Dioxide/toxicity
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Histones/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Inflammasomes/metabolism
• Inflammasomes/drug effects
• Cell Line
• Glycolysis/drug effects
• Phosphofructokinase-2/metabolism
• Phosphofructokinase-2/genetics
• Bronchi/drug effects
• Bronchi/pathology
• Bronchi/metabolism

• Development
• Diagnosis
• Gastrointestinal cancer
• Regulation
• Sine oculis homeobox homolog
• Therapeutics
• Transcription factor

• Eya proteins
• Metastasis
• Protein phosphatase 2A
• Serine/threonine phosphatase
• Transcriptional co-factor
• Tyrosine phosphatase

• Humans
• Neoplasms/genetics
• Neoplasms/pathology
• Neoplasms/metabolism
• Protein Tyrosine Phosphatases/metabolism
• Protein Tyrosine Phosphatases/genetics
• Animals
• Gene Expression Regulation, Neoplastic
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/genetics
• Eye Proteins/metabolism
• Eye Proteins/genetics
• Nuclear Proteins/metabolism
• Nuclear Proteins/genetics

• R01 NS108396 NINDS NIH HHS
• F30 CA257215 NCI NIH HHS
• R01 CA224867 NCI NIH HHS
• R01 CA221282 NCI NIH HHS
• R01 CA275187 NCI NIH HHS
• T32 CA174648 NCI NIH HHS
• F31 CA275314 NCI NIH HHS
• R35 GM145289 NIGMS NIH HHS

• Chemoresistance
• Epithelial-mesenchymal transition
• TEAD4
• Tumor microenvironment
• cancer metastasis

• Humans
• Drug Resistance, Neoplasm
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Epithelial-Mesenchymal Transition/physiology
• Tumor Microenvironment
• TEA Domain Transcription Factors

• Biomarker
• Cancer
• MiR-185
• MicroRNA
• MicroRNA-185

• Humans
• MicroRNAs/genetics
• Neoplasms/genetics
• Cell Line
• Clinical Relevance
• Down-Regulation

• PLAGL2
• Serous ovarian cancer
• TEAD4

• No. RC190500 Shenyang Young and Middle-aged Innovation Support Project
• No. 2020-MS-063 Natural Science Foundation of Liaoning Province

• Cancer
• Chronic kidney disease
• Coronary artery disease
• DACH1
• EYA1
• Organ development
• SIX1
• The retinal determinant gene network

The distant metastasis is the primary cause of cancer morbidity and mortality for bladder cancer (BLCA) paitents. All the recommended therapy for it largely depends on how far the cancer has invaded. It has been confirmed that epithelial to mesenchymal transition (EMT) is the leading reason for the BLCA metastasis which makes BLCA difficult to cure. The aim of the present study is to identify the BLCA-related genes that can be used as the new prognostic biomarker and treatment target, and to investigate the functional mechanisms of TEAD4 in EMT dysregulation.

The "limma" R package was used to identify the differentially expressed genes (DEGs) between the normal and the tumor samples from TCGA BLCA and GTEx databases. Kaplan–Meier and UniCox analysis were used to filter DEGs with prognostic value in BLCA. Step muti-Cox analysis was used to construct a prognostic risk score model based on clinical phenotype characters. Gene set enrichment analysis (GSEA) was performed to explore the possible molecular mechanisms affecting the prognosis in BLCA. Unsupervised hierarchical clustering analysis was performed to evaluate the effects of EMT process on the prognosis. Single-sample GSEA (ssGSEA) was used to calculate the correlation betweeen the expression of DEGs and EMT enrichment scores. TEAD4 expression and its association with pathological grading and survival were appraised in samples from TCGA dataset and BLCA tissue microarray. Colony formation assays and CCK8 assays were performed to study the changes in BLCA cell proliferation when the TEAD4 levels was down- or up-regulated in BLCA cells. Transwell and wound healing assays were utilized to analyze the impact of TEAD4 on the invasion and metastasis of the BLCA cells. Western Blot was carried out to detect the changes of EMT-related markers and the active molecules involved in PI3K/AKT signaling in BLCA cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was conducted on the genes related to TEAD4 expression. 740Y-P (activator of PI3K/AKT pathway) and LY294002 (inhibitor of PI3K/AKT pathway) were applied to evaluate the contribution of PI3K/AKT signaling pathway in the EMT of BLCA cells. To examine the in vivo effect of TEAD4 on tumor metastasis, we designed a metastatic nude-mouse model by tail vein injection of TEAD4-knockdown BLCA cells. And PET/CT imaging was used to assess the extent of lung metastases.

A total of 1592 DEGs were recognized, among which 4 DEGs have been identified as independent prognostic factors for BLCA, such as FASN, IGFL2, PLOD1 and TEAD4. TCGA BLCA samples were divided into significantly different low- and high-risk groups according to the median risk score; GSEA analysis showed that HALLMARK EMT pathway was the top enriched gene signature when compared high-risk and low-risk groups, which was also verified by unsupervised cluster analysis. EMT signature-derived ssGSEA scores demonstrated that TEAD4 had the most positive correlation with EMT process. In addition, TEAD4 expression was upregulated in TCGA BLCA samples and correlated with pT stage, tumor stage and tumor grade. Functional studies showed that TEAD4 knockdown via lentiviral TEAD4 shRNA inhibited cell migration and invasion in vitro and in vivo, with the reduced expression of EMT related markers in BLCA cell lines; the migration and invasion of TEAD4 knockdown cells could be restored by ectopic expression of TEAD4. Meanwhile, KEGG enrichment analysis of genes related to TEAD4 expression showed that enrichment was significantly related to PI3K/AKT pathway. The pathway inhibitor LY294002 blocked the TEAD4-induced enhancement of migration and invasion as well as the expression EMT-related markers, whereas the agonist 740Y-P rescued the decreased migration, invasion and EMT induced by TEAD4 knockdown.

TEAD4 is closely correlated with poor prognosis in BLCA and mediates its metastasis through regulating EMT via PI3K/AKT pathway, proving that TEAD4 is not only an effective biomarker for predicting the prognosis but also a great potential target for treatment of metastatic BLCA.

The online version contains supplementary material available at 10.1186/s13046-022-02377-3.

• AKT
• Bladder cancer
• EMT
• PI3K
• TEAD4

TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4’s functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.

• Hippo pathway
• TEAD family
• expression profiles
• immune infiltration
• ovarian serous carcinoma
• prognosis

• the China Postdoctoral Science Foundation
• the National Natural Science Foundation of China
• the Natural Science Foundation of Hunan Province
• the Postdoctoral Science Foundation of Central South University

The transcription factor cyclic-AMP response element-binding protein 1 (CREB1) responds to cAMP level and controls the expression of target genes, which regulates nutrition partitioning. The promoters of CREB1-targeted genes responsive to cAMP have been extensively investigated and characterized with the presence of both cAMP response element and TATA box. Compelling evidence demonstrates that CREB1 also plays an essential role in promoting tumor development. However, only very few genes required for cell survival, proliferation and migration are known to be constitutively regulated by CREB1 in tumors. Their promoters mostly do not harbor any cAMP response element. Thus, it is very likely that CREB1 regulates the expressions of distinct sets of target genes in normal tissues and tumors. The whole gene network constitutively regulated by CREB1 in tumors has remained unrevealed. Here, we employ a systematical and integrative approach to decipher this gene network in the context of both tissue cultured cancer cells and patient samples. We combine transcriptomic, Rank-Rank Hypergeometric Overlap, and Chipseq analysis, to define and characterize CREB1-regulated genes in a multidimensional fashion. A strong cancer relevance of those top-ranked targets, which meet the most stringent criteria, is eventually verified by overall survival analysis of cancer patients. These findings strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis.

• CREB1
• Cancer
• Kaplan–Meier analysis
• RRHO
• Transcription factor