Bioinformatics Analysis Reveals Esophageal Squamous Cell Carcinoma-Associated Lysine-Related Genes as Poor Prognostic Factors and Potential Therapeutic Targets

Abstract

Background: Esophageal squamous cell carcinoma (ESCC) represents a prevalent malignancy within the digestive tract, often diagnosed at advanced stages, leading to treatment challenges and poor prognosis. Despite its essential roles in biosynthesis, antioxidation, and energy metabolism, the involvement of lysine in cancer pathogenesis remains poorly understood. This study aimed to elucidate the significance of lysine-associated genes in ESCC, potentially enhancing treatment outcomes. Methods: mRNA expression data for ESCC were retrieved from The Cancer Genome Atlas (TCGA) for limma differential expression analysis. Lysine-related genes were extracted from the GeneCards database and overlapped with differentially expressed genes. Lysine levels were quantified using single-sample Gene Set Enrichment Analysis (ssGSEA), followed by metabolic pathway analysis comparing high and low lysine levels. The random survival forest (RSF) algorithm identified lysine-related genetic signatures associated with poor prognosis of ESCC. Further analysis encompassed drug susceptibility profiling and assessment of immune cell infiltration. Subsequently, single-cell analysis was conducted using data from the Gene Expression Omnibus (GEO) database (GSE196756) to validate key lysine-related genes. Results: Ubiquitination Factor E4A (UBE4A) and Apolipoprotein C1 (APOC1) were identified as key lysine-associated genes in ESCC. Functional enrichment analysis revealed that the lysine-related genes remarkably enriched lysine-regulated pathways, including histone modification, histone lysine methylation, and lysine degradation pathways. Moreover, these lysine-related differentially expressed genes (DEGs) served as independent prognostic factors, and a nomogram incorporating these genes and clinical factors accurately predicted 1- and 2-year survival rates in ESCC patients. Drug databases highlighted AICAR, BI.D1870, MS.275, and lapatinib as potential therapeutic agents. Immunemicroenvironment infiltration analysis indicated that UBE4A was actively connected with T cells CD4 memory resting and passively connected with B cells memory. APOC1 was actively linked to macrophages M2, T cells CD4 memory activated, T cells CD8, and was passively linked to the activated Dendritic cells, T cells CD4 memory resting and Eosinophils. We further performed single-cell analysis, and 21 subtypes were obtained by t-Distributed Stochastic Neighbor Embedding (tSNE) algorithm. The total clusters were labeled to tissue stem cells, neurons, epithelial cells, B cells, neutrophils, monocytes, T cells, smooth muscle cells, NK cells, and endothelial cells. Conclusions: Our findings underscore the pivotal role of lysine-related gene regulation in ESCC. The identified lysine-related genes hold promise as prognostic indicators for ESCC patients, shedding light on potential mechanisms underlying poor prognosis and facilitating the search for targeted therapeutics to enhance the success rate of ESCC treatment.