Multi-omics analysis of core E3 ubiquitin ligase identifies prognostic biomarkers associated with immune infiltration and drug sensitivity in lung adenocarcinoma.

Abstract

Background: Ubiquitination is involved in several tumor immunomodulatory processes, and targeting E3 ubiquitin ligases has substantial potential in cancer therapy. Methods: In this study, the key E3 ubiquitin ligases involved in regulating the malignant progression of LUAD were studied. We first systematically investigated the expression landscape, prognosis, immune infiltration, drug sensitivity, and potential molecular mechanisms of these hub genes in LUAD. CDC20 was localized by immunofluorescence analysis in tumor cell lines, and its expression level was determined by immunohistochemistry on tissue chips. Single-cell analysis and spatial transcriptomics were used to determine CDC20 expression in multiple cell types. Molecular docking was performed via computer simulation to verify the ability of drugs to bind to target genes. Results: We found that these hub genes are specifically overexpressed in LUAD and are associated with poor patient prognosis. All five E3 ubiquitin ligase genes were negatively correlated with B cells and dendritic cells but positively related to neutrophil immune infiltration. In addition, analysis of the CTRP and GDSC databases revealed that the sensitivity to multiple antitumor drugs increased when CCNF was highly expressed. GSEA enrichment analysis demonstrated that the G2M_CHECKPOINT, MTORC1_SIGNALING, OXIDATIVE_PHOSPHORYLATION, and GLYCOLYSIS signaling pathways were enriched when CDC20 was highly expressed. Further correlation analysis indicated that CDC20 was positively correlated with the expression of the key genes mTOR, S6K1, and 4E-BP1 and the autophagy-related gene ULK1 in the mTORC1 signaling pathway. Conclusions: These key E3 ubiquitin ligases serve as potential molecular biomarkers for predicting the prognosis, immune response, and drug sensitivity of LUAD patients.