5-Azacytidine promotes invadopodia formation and tumor metastasis through the upregulation of PI3K in ovarian cancer cells.

The high incidence of metastasis accounts for most of the lethality of ovarian cancer. Invadopodia are small, specialized types of machinery that degrade the extracellular matrix and are thus involved in the invasion and metastasis of cancer cells. The formation of invadopodia is regulated by both genetic and epigenetic factors. However, the ways by which methylation/demethylation regulates the dynamics of invadopodia in ovarian cancer are largely unknown. In this study, we found that the inhibition of methylation by 5-AZ (5-Azacytidine) increased the formation of invadopodia and enhanced degradation of the extracellular matrix in ovarian cancer cells. In mouse xenograft models, treatment with 5-AZ increased the number of metastatic nodules, which suggests an elevated potential for metastasis by demethylation. Further investigation indicated that the inhibition of methylation elevated the transcription of PIK3CA and upregulated genes involved in the PI3K-AKT signaling pathway. In addition, this induction likely occurs though the epigenetic regulation of PIK3CA because analyses of the DNA methylation level of the PIK3CA promoter region found that 5-AZ treatment decreased the methylation of CpG islands in SKOV3 and A2780 cells. Our study demonstrated that epigenetic factors regulate the metastatic potential of ovarian cancer cells and provide rationale for therapies that inhibit PI3K- invadopodia-mediated metastasis.