Roles of cuproptosis-related gene DLAT in various cancers: a bioinformatic analysis and preliminary verification on pro-survival autophagy

Background: Studies have shown that the expressions and working mechanisms of Dihydrolipoamide S-acetyltransferase (DLAT) in different cancers vary. It is necessary to analyze the expressions and regulatory roles of DLAT in tumors systematically.

Methods: Online public-platform literature on the relationships between DLAT expression levels and tumor prognosis, methylation status, genetic alteration, drug sensitivity, and immune infiltration has been reviewed. The literature includes such documents as The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA), Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and Receiver Operating Characteristic plotter (ROC plotter). The molecular mechanisms of DLAT were explored with the Gene Set Enrichment Analysis (GSEA). The relationship between down-regulated DLAT and autophagy in two liver hepatocellular carcinoma (LIHC) cell lines was confirmed with the western blot method, colony formation assay, and transmission electron microscopy. Tissue microarrays were validated through the immunohistochemical staining of DLAT.

Results: DLAT is upregulated in the LIHC, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and stomach adenocarcinoma (STAD) tumors but is down-regulated in the head and neck squamous cell carcinoma (HNSC) and kidney renal clear cell carcinoma (KIRC) tumors in comparison with normal tissues. For LIHC patients treated with 5-Fluorouracil and Lenvatinib, the DLAT levels of those in the drug-resistant group are significantly high. In LIHC cells, autophagy will be inhibited, and cell death will be induced when DLAT breaks down. Moreover, there exist positive correlations between DLAT expression levels and infiltration of B cells, DC cells, Tregs, and CD8+ T cells in kidney chromophobe (KICH), breast invasive carcinoma (BRCA), prostate adenocarcinoma (PRAD), LIHC and HPV+ HNSC. In LIHC, markers of Tregs are positively correlated with DLAT. Compared with those of normal tissues, the staining intensity of DLAT and the amount of Tregs marker CD49d in LIHC increase.

Conclusions: Through this study, the expressions of DLAT in various cancer types can be understood comprehensively. It suggests that DLAT may be a prognostic marker for LIHC, LUAD, LUSC, STAD and KIRC. A high DLAT expression in LIHC may promote tumorigenesis by stimulating autophagy and inhibiting anti-tumor immunity.