Multi-omics and pharmacological analyses identify DDX60 as a candidate EGCG-engaged target in esophageal squamous cell carcinoma.
Abstract
Esophageal squamous cell carcinoma (ESCC) is highly aggressive with limited available biomarkers, and discovering causative, functionally significant, and pharmacologically tractable targets is fundamental for new intervention strategies. By integrating Mendelian randomization, multi-cohort transcriptomic validation, single-cell analysis, and experimental pharmacology, DDX60 was identified as a key candidate gene associated with ESCC. The two-sample MR integrating eQTLGen, IEU OpenGWAS, and FinnGen datasets identified DDX60 as a key gene associated with esophageal cancer. Multi-omics utilizing TCGA, GTEx, cfDNA 5hmC profiling, and paired clinical ESCC specimens validated DDX60 expression in ESCC. Single-cell RNA-seq showed DDX60 enrichment in tumor-derived malignant epithelial cells versus matched normal epithelium. Epithelial cells expressing high DDX60 displayed enhanced epithelial-mesenchymal transition (EMT) and interferon-response signatures, accompanied by a slightly elevated PI3K/AKT/mTOR pathway score and progression along the malignant epithelial trajectory. Functionally, silencing DDX60 in ESCC cells increased apoptosis, decreased the phosphorylation of PI3K, AKT, and mTOR, and inhibited migration and invasion. These results demonstrated the role of DDX60 in ESCC progression. To explore potential pharmacological modulation of DDX60, PheWAS- and DSigDB-guided compound screening, molecular docking, and molecular dynamics simulation were performed, identifying epigallocatechin-3-gallate (EGCG) as a candidate DDX60-associated compound. EGCG reduced ESCC cell viability, decreased the levels of DDX60 protein, and enhanced the thermal stability of endogenous DDX60 in cell-based CETSA assays. Analysis using DDX60-knockdown cells further suggested that DDX60 status may influence cellular responsiveness to EGCG. Conclusively, DDX60 demonstrated considerable potential as an exploitable target in ESCC, amenable to modulation by EGCG through the disruption of DDX60-associated oncogenic mechanisms.
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