LAUSR

BACKGROUND Increasing evidence indicates that an imbalance of oncogenes is implicated in chemotherapy resistance in cancers. Methyl-CpG binding protein 2 (MeCP2), which acts as a master epigenetic regulator of various gene expressions, is involved in the carcinogenesis and progression of gastric cancer. However, whether this vital role may participates in acquired cisplatin resistance in GC remains unknown. OBJECTIVE This study aimed to determine whether inhibition of MeCP2 expression could sensitize DDP-resistant GC cells to DDP and to elucidate its underlying molecular mechanism. METHODS qRT-PCR and western blotting were used to evaluate MeCP2 expression in GC DDP-resistant GC cells. Subsequently, cell viability, colony formation, cell cycle, cell apoptosis and tumorigenicity assays were performed to explore the role of MeCP2 in vitro and in vivo. Chromatin immunoprecipitation-qPCR and luciferase reporter assays were used to identify whether 3-phosphoinositide-dependent protein kinase 1 (PDK-1) is a direct target gene of MeCP2. RESULTS MeCP2 was upregulated in malignant DDP-resistant cells compared to that in non-DDP-resistant GC cells or normal gastric epithelial cells. MeCP2 knockdown increased the sensitivity of DDP-resistant GC cells to DDP, resulting in reduced cell growth, G0/G1 phase arrest and increased apoptosis, wheras MeCP2 overexpression attenuated DDP sensitivity of DDP-resistant GC cells. In addition, MeCP2 knockdown enhanced DDP sensitivity in tumors in vivo. MeCP2 elevated PDK-1 expression by binding to its CpG sites in promoter regions, and inhibition of PDK-1 reversed the inductive effect of MeCP2 overexpression on DDP resistance in GC cells. CONCLUSION These findings indicate that silencing MeCP2 may potentiate DDP induced cell death, providing a promising therapeutic strategy for GC.