Abstract

MEIS2 is downregulated and hypermethylated in gastric cancer tissues. • Low MEIS2 associates with advanced stage, neural invasion, and poor prognosis. • MEIS2 suppresses tumor growth by inhibiting proliferation, invasion, and glycolysis. • DNMT1 binds MEIS2 promoter (−811 to −757 bp) to induce methylation, reversible by 5-Aza. Background Gastric cancer (GC) is a molecularly heterogeneous disease with poor prognosis. DNA methylation plays a critical role in its pathogenesis, and Homeobox genes are known to be frequently dysregulated through epigenetic mechanisms in various cancers. However, the role of the homeobox gene MEIS2 in GC remains unclear. Method Integrated bioinformatics analysis of RNA-seq and DNA methylation data from TCGA and a K19-Wnt1/C2mE transgenic ( Gan ) mouse model identified MEIS2 as a candidate gene. Its clinical relevance was assessed using GEO datasets and a clinical cohort of 293 GC patients. Functional roles were investigated through in vitro assays, RNA-seq, and metabolic analyses. Methylation-specific PCR, MassARRAY, and ChIP were used to explore the regulatory mechanisms. Results MEIS2 was significantly downregulated in GC tissues, and its low expression was associated with advanced tumor stage, neural invasion, and poor overall survival. Functional experiments demonstrated that MEIS2 overexpression suppressed GC cell proliferation, migration, and invasion, induced apoptosis, and inhibited glycolysis by reducing glucose uptake, lactate production, and the expression of key glycolytic enzymes. Hypermethylation of the MEIS2 promoter region (−811 to −757 bp) was negatively correlated with its expression. DNMT1 was found to bind directly to this region and promote MEIS2 promoter hypermethylation, leading to its transcriptional downregulation. Conclusion MEIS2 acts as a tumor suppressor in GC, and its downregulation is mediated by DNMT1-driven promoter hypermethylation. These findings highlight MEIS2 as a potential therapeutic target and pro