Regulation of epithelial‐mesenchymal transition and apoptosis by dual specificity phosphatase‐2

Our previous findings provide evidence to demonstrate that dual specificity phosphatase‐2 (DUSP2) is markedly reduced or even lost in most solid cancers. To further unravel the effect of DUSP2 downregulation in cancer progression, we overexpressed DUSP2 in cancer cells and performed microarray assay to document gene expression profile. Analysis of microarray data derived from DUSP2 overexpressed cancer cells revealed that many genes involved in angiogenesis, epithelial‐mesenchymal transition (EMT), cell migration, and apoptosis are regulated by DUSP2. Since EMT is a critical process for an increase in metastatic capacity and drug resistance, we tested whether loss‐of‐function of DUSP2 would induce EMT. Knock down of DUSP2 induced the expression of mesenchymal markers (N‐cadherin) and reduced the level of epithelial marker (E‐cadherin). Consistent with this notion, treatment with conditioned media collected from DUSP2 knockdown cells enhanced cancer cells migration while treatment with conditioned medium collected from DUSP2 overexpressed cells inhibited cell migration. Furthermore, we established a stable clone of HCT116 cells carrying doxycycline‐inducible DUSP2 minigene. Treatment of cells with doxycycline to induce DUSP2 expression resulted in upregulation of pro‐apoptotic genes such as Bcl2‐modifying factor and endonuclease/exonuclease/phosphatase family domain‐containing protein 1. As expect, induction of DUSP2 expression increased cell death. These data suggest that restoration of DUSP2 expression in cancer cells represents a potential therapeutic approach. In‐depth investigation of mechanisms responsible for DUSP2‐induced cell death will provide valuable information for designing novel treatment regimen for cancer therapy.