Down-regulation of dual-specificity phosphatase 5 in gastric cancer by promoter CpG island hypermethylation and its potential role in carcinogenesis.

Dual-specificity phosphatase 5 (DUSP5), which regulates the duration and magnitude of ERK1/2 phosphoactivation within the mitogen-activated protein kinase (MAPK) cascade, has recently been proposed to be a tumor suppressor. However, the epigenetic regulation of DUSP5 and its critical roles in gastric cancer (GC) remain unknown. We compared differential RNA expression profiles of GC cell lines with or without treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine. DUSP5 expression was dramatically decreased by DNA methylation. Hypermethylation of the DUSP5 promoter was detected in GC tissue samples, but not in normal healthy gastric mucosa samples. Restoring DUSP5 expression in DUSP5-silenced GC cell lines decreased their growth and colony-forming ability by causing arrest in the transition from G1 to S phase in the cell cycle as a result of dephosphorylation of ERK1/2 in the nucleus. Moreover, in a set of surgically resected GC cases (n = 179), GCs with DUSP5 promoter region hypermethylation (30.2%) exhibited significantly shortened survival, compared with GCs without DUSP5 methylation (P = 0.009). These results suggest that silencing of DUSP5 by promoter hypermethylation causes increased maintenance of phosphorylated ERK1/2, driving cell proliferation and contributing to gastric carcinogenesis. Furthermore, DUSP5 methylation may serve as a prognostic marker for GC, but this requires validation in a larger set of GC samples.