NSUN6 Promotes Gastric Cancer Progression by Stabilizing CEBPZ mRNA in a mC-Dependent Manner.

Gastric cancer (GC) is a malignant tumor originating from the epithelial cells of the gastric mucosa. The 5-methylcytosine (mC) modification refers to the addition of a methyl group to the fifth carbon atom of cytosine in RNA molecules. This study aimed to investigate the role of NOL1/NOP2/SUN domain (NSUN)6 in GC and its underlying molecular mechanisms. Human gastric mucosa cells and gastric cancer cells were used for in vitro experiments. mC level was quantified using dot blot analysis. Cell viability and proliferation were evaluated via cell counting kit-8 and colony formation assays. Apoptosis rates were analyzed by flow cytometry. Autophagy-related protein expression was detected through Western blot analysis. The interaction between NSUN6 and CCAAT/Enhancer Binding Protein Zeta (CEBPZ) was validated by RNA immunoprecipitation. Results demonstrated that NSUN6 functioned as an oncogene in GC. Furthermore, NSUN6 inhibition suppressed GC cell proliferation while promoting apoptosis and autophagy. CEBPZ was identified as a target gene of NSUN6 in GC through bioinformatic analysis. Mechanistically, NSUN6 enhanced CEBPZ mRNA stability via mC methylation. Subsequent rescue experiments revealed that CEBPZ overexpression increased cell proliferation and reduced apoptosis and autophagy in GC. Additionally, NSUN6-mediated mC methylation of CEBPZ suppressed autophagy by activating the p53/mTOR pathway. In conclusion, NSUN6 promoted GC progression by stabilizing CEBPZ mRNA in an mC-dependent manner. However, further in vivo and clinical studies are warranted to validate these findings and explore their translational potential.