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 between pPAK4 and pSlugS158 but an inverse correlation between pSlugS158 and E-cadherin. The results suggest that the PAK4–Slug axis represents a novel pathway that promotes PC progression.

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Acknowledgements

This work was supported in part by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A2B3005714 and 2015R1A2A2A04004251), International Science and Business Belt Program through the Ministry of Science, ICT (2017K000490), and Chungbuk National University grant (2015).

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Correspondence to Eun-Young Shin or Eung-Gook Kim.

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