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

Abstract

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.

METTL3 as a novel diagnosis and treatment biomarker and its association with glycolysis, cuproptosis and ceRNA in oesophageal carcinoma

“…Through our analysis of TCGA ESCA and GSE63941 data sets, we found a correlation only between expression levels of DLAT and METTL3. Furthermore, we observed that DLAT expression was significantly higher in tumour samples compared to normal samples, consistent with previous reports indicating DLAT upregulation in various types of cancer such as LIHC, LUAD, LUSC, PAAD and STAD [72][73][74][75]. Additionally, we found that DLAT expression was significantly higher in the high METTL3 expression group than in the low expression group, highlighting the potential association between these two genes in cuproptosis-related tumour development.…”

Comprehensive molecular analyses of cuproptosis-related genes with regard to prognosis, immune landscape, and response to immune checkpoint blockers in lung adenocarcinoma

“…The relationships between DLAT and various types of tumors have been extensively studied. It has been found that mRNA levels of DLAT are significantly higher in tumor tissues of liver hepatocellular carcinoma and stomach adenocarcinoma compared to normal tissues, whereas they are lower in head and neck squamous cell carcinoma and kidney renal clear cell carcinoma (Yang et al 2023). DLAT expression has also been identified as a prognostic factor in several cancers, where higher levels are associated with poorer survival outcomes (Xu et al 2023).…”

Immunomodulation of cuproptosis and ferroptosis in liver cancer

“…Additionally, a study has shown a correlation between cuproptosis-related dihydrolipoamide S-acetyltransferase (DLAT) and CD49d, which is one of the typical phenotype markers of Tregs. The high expression of DLAT may increase the immune infiltration of Tregs; thus, tumorigenesis and tumor invasion are ultimately promoted [ 62 ]. In sum, both cuproptosis and ferroptosis are involved in the regulation of TME in liver cancer; but for now, few currently verify the effect of cuproptosis federation with ferroptosis on TME in liver cancer.…”