AUTHOR=Gong Xiaoxia , Li Ning , Sun Chen , Li Zhaoshui , Xie Hao 

TITLE=A Four-Gene Prognostic Signature Based on the TEAD4 Differential Expression Predicts Overall Survival and Immune Microenvironment Estimation in Lung Adenocarcinoma

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.874780

DOI=10.3389/fphar.2022.874780

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> TEA domain transcription factor 4 (TEAD4) is a member of the transcriptional enhancer factor (TEF) family of transcription factors, which is studied to be linked to the tumorigenesis and progression of various forms of cancers, including lung adenocarcinoma (LUAD). However, the specific function of this gene in the progression of LUAD remains to be explored.</p><p><bold>Method:</bold> A total of 19 genes related to the Hippo pathway were analyzed to identify the significant genes involved in LUAD progression. The TCGA-LUAD data (n = 585) from public databases were mined, and the differentially expressed genes (DEGs) in patients with the differential level of <italic>TEAD4</italic> were identified. The univariate Cox regression, zero LASSO regression coefficients, and multivariate Cox regression were performed to identify the independent prognostic signatures. The immune microenvironment estimation in the two subgroups, including immune cell infiltration, HLA family genes, and immune checkpoint genes, was assessed. The Gene Set Enrichment Analysis (GSEA) and GO were conducted to analyze the functional enrichment of DEGs between the two risk groups. The potential drugs for the high-risk subtypes were forecasted <italic>via</italic> the mode of action (moa) module of the connectivity map (CMap) database.</p><p><bold>Results:</bold><italic>TEAD4</italic> was found to be significantly correlated with poor prognosis in LUAD-patients. A total of 102 DEGs in <italic>TEAD4</italic>-high vs. <italic>TEAD4</italic>-low groups were identified. Among these DEGs, four genes (<italic>CPS1</italic>, <italic>ANLN</italic>, <italic>RHOV</italic>, and <italic>KRT6A</italic>) were identified as the independent prognostic signature to conduct the Cox risk model. The immune microenvironment estimation indicated a strong relationship between the high <italic>TEAD4</italic> expression and immunotherapeutic resistance. The GSEA and GO showed that pathways, including cell cycle regulation, were enriched in the high-risk group, while immune response-related and metabolism biological processes were enriched in the low-risk group. Several small molecular perturbagens targeting <italic>CFTR</italic> or <italic>PLA2G1B</italic>, by the mode of action (moa) modules of the glucocorticoid receptor agonist, cyclooxygenase inhibitor, and NFkB pathway inhibitor, were predicted to be suited for the high-risk subtypes based on the high <italic>TEAD4</italic> expression.</p><p><bold>Conclusion:</bold> The current study revealed <italic>TEAD4</italic> is an immune regulation–related predictor of prognosis and a novel therapeutic target for LUAD.</p>