Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and metastasis and thus accelerates cancer progression. p21-activated kinase 4 (PAK4) is a critical regulator of prostate cancer (PC) progression. Here， we report that PAK4 activation promotes PC progression through the EMT regulator Slug. We find that phosphorylated PAK4 (pPAK4) levels， an index of PAK4 activation， were tightly associated with Gleason score (p < 0.001)， a clinical indicator of PC progression， but not with prostate serum antigen levels or tumor stage. Stable silencing of PAK4 in PC cells reduced their potential for EMT， cellular invasion， and metastasis in vivo. PAK4 bound and directly phosphorylated Slug at two previously unknown sites， S158 and S254， which resulted in its stabilization. The non-phosphorylatable form Slug upregulated transcription of CDH1， which encodes E-cadherin， and thus suppressed EMT and invasion， to a greater extent than did wild-type Slug. The strong EMT inducer TGF-β elevated pPAK4 and pSlug levels; PAK4 knockdown or introduction of a dominant-negative form of PAK4 inhibited both TGF-β-stimulated EMT and an increase in pSlug levels. Finally， immunohistochemistry revealed a positive correlation between pPAK4 and pSlug but an inverse correlation between pSlug and E-cadherin. The results suggest that the PAK4-Slug axis represents a novel pathway that promotes PC progression.