DNA methylation inhibitor, decitabine, promotes MGC803 gastric cancer cell migration and invasion via the upregulation of NEDD4­1.

ABSTRACT

Gastric cancer is the fourth most common cancer type and the second leading cause of cancer­associated mortality worldwide. Metastasis is a crucial feature of its progression. DNA methylation provides a key epigenetic signature in the epigenetic regulation pathway, and is implicated in transcriptional regulation. CpG sites, which are associated with gene transcriptional activity, are underrepresented in the mammalian genome and tend to be clustered within CpG islands (CGIs) located in the vicinity of the transcription start sites of the majority of the protein­coding genes in humans. The DNA methylation inhibitor, decitabine (DAC), has been demonstrated to be active in hematological disorders. The majority of previous studies in cancer cells demonstrated that DAC inhibits cell proliferation and the motility of the cells. However, since demethylation across the entire genome alters the expression of a large number of genes, the effects of DAC in different tumor cell types are difficult to accurately predict. Neural precursor cell­expressed, developmentally downregulated (NEDD)4­1, a member of the NEDD4 family, which belongs to the E3­ubiquitin ligase family, was reported to be highly expressed in a wide range of tumor types, and it activates the phosphoinositide 3­kinase/Akt pathway by degrading phosphatase and tensin homolog. NEDD4­1 promotes the migration and invasion of glioma cells via the ubiquitination and subsequent degradation of cyclic nucleotide­Ras guanine nucleotide exchange factors (CNrasGEFs). In gastric cardia adenocarcinoma, NEDD4­1 acts as an exceptional prognostic biomarker. In the present study, DAC was revealed to promote the invasive properties of MGC803 gastric cancer cells. NEDD4­1 targeted the CNrasGEF­mediated DAC invasion­promoting activity in MGC803 cells, and CGI methylation in neither the NEDD4 promoter nor the first intron was demonstrated to be associated with this effect. The results of the present study revealed that DAC exerts variable effects in different gastric cancer cell lines and may provide a reference for DAC administration in the clinic.