DNA methyltransferase 3A: A prognostic biomarker and potential target for immunotherapy in gastric cancer

DNA methyltransferase 3A (DNMT3A) has been associated with the occurrence or progression of various tumors, including gastric cancer. However, the role of DNMT3A in the efficacy of immune-cell infiltration in the tumor microenvironment and immunotherapy in gastric cancer remains less explored. DNMT3A expression level was analyzed using TIMER 2.0, Sangerbox 3.0, and The Cancer Genome Atlas database and further verified by immunohistochemical staining and RT-qPCR. The UALCAN, chi-square test, and Kaplan-Meier plotter databases were performed to assess the correlation of DNMT3A with clinicopathological characteristics and prognosis. The GeneMANIA database, STRING database, and R package were used to construct a DNMT3A co-expression gene network. Gene set enrichment analysis was used to identify the signaling pathways related to DNMT3A expression. The correlations between DNMT3A and cancer immune infiltrates were investigated using TIMER 2.0, Sangerbox 3.0, Kaplan-Meier Plotter, R package, and TISIDB databases. The TISIDB database and R package were used to construct the correlation between DNMT3A and immunomodulators and Immune cell Proportion Score. The association of DNMT3A expression with tumor mutational burden (TMB), microsatellite instability, and tumor dryness was evaluated using the TMB function of the R package, TIMER 2.0. Finally, the biological function of DNMT3A in gastric cancer cells was further assessed by CCK-8, cloning formation, and transwell assay. DNMT3A expression was remarkably upregulated in gastric cancer. The high expression of DNMT3A was associated with poor clinical features and poor survival in patients with gastric cancer. Moreover, gene set enrichment analyses showed that DNMT3A and its related genes were involved in various pathways that promoted cancer occurrence and progression by influencing the tumor microenvironment. Finally, DNMT3A was significantly related to tumor-infiltrating immune cells, immunomodulators, TMB, microsatellite instability, and immune checkpoints in gastric cancer. Moreover, knockdown of DNMT3A reduced the proliferation and migration of gastric cancer cells. Our findings highlight the potential of DNMT3A as a prognosis biomarker and an immunotherapeutic target for gastric cancer.