The p21-activated kinase 4-Slug transcription factor axis promotes epithelial-mesenchymal transition and worsens prognosis in prostate cancer
Abstract
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 PAK4S474 (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 SlugS158A/S254A 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 pSlugS158 levels; PAK4 knockdown or introduction of a dominant-negative form of PAK4 inhibited both TGF-β-stimulated EMT and an increase in pSlugS158 levels. Finally, immunohistochemistry revealed a positive correlation be...Continue Reading
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CBP-mediated Slug acetylation stabilizes Slug and promotes EMT and migration of breast cancer cells.
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