Downregulation of Snail by DUSP1 Impairs Cell Migration and Invasion through the Inactivation of JNK and ERK and Is Useful as a Predictive Factor in the Prognosis of Prostate Cancer

SIMPLE SUMMARY: The role of dual specificity phosphatase 1 (DUSP1) in metastasis-associated processes in prostate cancer and its impact on patient outcome remains to be elucidated. Our results reveal that this phosphatase reduces Snail expression and impairs cell migration and invasion in prostate cancer cells through a mechanism involving the inhibition of DUSP1 molecular targets, c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK). In clinical samples, we evidence an inverse correlation between DUSP1 expression and Snail levels, which are further associated with JNK and ERK activation. Importantly, patients with the pattern DUSP1(high)/activated JNK(low)/activated ERK(low)/Snail(low) exhibit a longer time to progression and a better outcome than those with the opposite pattern. All these findings highlight new opportunities to improve current therapeutic strategies for the diagnosis and treatment of prostate cancer. ABSTRACT: Dual specificity phosphatase 1 (DUSP1) is crucial in prostate cancer (PC), since its expression is downregulated in advanced carcinomas. Here, we investigated DUSP1 effects on the expression of mesenchymal marker Snail, cell migration and invasion, analyzing the underlying mechanisms mediated by mitogen-activated protein kinases (MAPKs) inhibition. To this purpose, we used different PC cells overexpressing or lacking DUSP1 or incubated with MAPKs inhibitors. Moreover, we addressed the correlation of DUSP1 expression with Snail and activated MAPKs levels in samples from patients diagnosed with benign hyperplasia or prostate carcinoma, studying its implication in tumor prognosis and survival. We found that DUSP1 downregulates Snail expression and impairs migration and invasion in PC cells. Similar results were obtained following the inhibition of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK). In clinical samples, we evidenced an inverse correlation between DUSP1 expression and Snail levels, which are further associated with JNK and ERK activation. Consequently, the pattern DUSP1(high)/activated JNK(low)/activated ERK(low)/Snail(low) is associated with an overall extended survival of PC patients. In summary, the ratio between DUSP1 and Snail expression, with additional JNK and ERK activity measurement, may serve as a potential biomarker to predict the clinical outcome of PC patients. Furthermore, DUSP1 induction or inhibition of JNK and ERK pathways could be useful to treat PC.