NFATc4 Promotes Lung Adenocarcinoma Progression via the CCNB1/CDK1 Pathway and Is a Potential Prognostic Biomarker

ABSTRACT Nuclear factor of activated T‐cells, cytoplasmic 4 (NFATc4), a transcription factor of the NFAT family, has been reported to participate in the tumorigenesis and progression of several cancers. However, the function and regulation of NFATc4 in lung adenocarcinoma (LUAD) remain poorly understood. Here, we report for the first time that NFATc4 is significantly overexpressed in LUAD tissues, and high NFATc4 expression correlates with lymphatic metastasis, advanced tumor stage, and poor prognosis in patients. Subsequent functional studies revealed that NFATc4 depletion inhibits LUAD cell viability, proliferation, and tumor growth by inducing cell cycle arrest in the G2/M phase and apoptosis. A mechanistic study shows that NFATc4 knockdown leads to significant enrichment of cellular process‐related pathways and differentially expressed genes, especially downregulated genes Cyclin B1 (CCNB1) and cyclin‐dependent kinase 1 (CDK1). NFATc4 directly binds to the CCNB1 promoter to regulate the CCNB1/CDK1 pathway, resulting in cell cycle arrest and inhibition of cell proliferation. This study identifies NFATc4/CCNB1/CDK1 as a novel regulatory pathway involved in LUAD development and provides a potential prognostic biomarker and molecular therapeutic target for LUAD.