The p21-activated kinase 4-Slug transcription factor axis promotes epithelial-mesenchymal transition and worsens prognosis in prostate cancer

Oncogene
Jung-Jin ParkEung-Gook Kim

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

References

Jun 24, 2000·Molecular and Cellular Biology·K HemavathyY T Ip
Jul 2, 2003·Molecular and Cellular Biology·David DomínguezAntonio García de Herreros
Feb 18, 2004·Molecular and Cellular Biology·Lizhi ZhangDiane M Simeone
Oct 20, 2005·The Biochemical Journal·Ofelia M Martínez-EstradaSenén Vilaró
Nov 22, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jin-Yuan ShihPan-Chyr Yang
Mar 30, 2007·The Journal of Biological Chemistry·Ulrike E E RennefahrtJeffrey R Peterson
Jun 26, 2007·Cells, Tissues, Organs·Hyeonseok KoJong In Yook
May 19, 2009·Nature Cell Biology·Shu-Ping WangPan-Chyr Yang
Nov 11, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Meng-Lei Zhu, Natasha Kyprianou
Jun 23, 2010·BMC Cancer·Hong Wei YangMark D Johnson
Feb 2, 2011·Laboratory Investigation; a Journal of Technical Methods and Pathology·Kejun ZhangDongsheng Wang
Jun 22, 2011·Nature Reviews. Urology·Jones T Nauseef, Michael D Henry
Sep 27, 2012·Proceedings of the National Academy of Sciences of the United States of America·Zhao-Qiu WuStephen J Weiss
Dec 1, 2012·Current Opinion in Oncology·Yoko KatsunoRik Derynck
Jan 31, 2013·The Journal of Biological Chemistry·Huibin YangDiane M Simeone
Apr 27, 2013·Biochemical and Biophysical Research Communications·Hildegonda P H NaberTheo van Laar
Jun 2, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Mousumi TaniaJunjiang Fu
Aug 27, 2014·Proceedings of the National Academy of Sciences of the United States of America·Maurizio RisolinoPasquale Verde
Sep 16, 2014·International Journal of Cancer. Journal International Du Cancer·Jacques FerlayFreddie Bray
Apr 10, 2015·Cancer Research·Reetta VirtakoivuJohanna Ivaska
Nov 10, 2015·Future Oncology·Seth A Broster, Natasha Kyprianou
Jan 16, 2016·Urology·Janine Hensel, George N Thalmann
May 18, 2016·The Journal of Steroid Biochemistry and Molecular Biology·Mary Nakazawa, Natasha Kyprianou
Nov 15, 2016·Stem Cells International·Megan MladinichChia-Hsin Chan

❮ Previous
Next ❯

Citations

Aug 2, 2020·Science China. Life Sciences·Xiaoyan DaiHongquan Zhang
Feb 14, 2019·Experimental & Molecular Medicine·So-Yoon WonEung-Gook Kim
Oct 15, 2020·Scientific Reports·Zlata VershininDan Levy

❮ Previous
Next ❯

Methods Mentioned

BETA
xenograft
ubiquitination

Software Mentioned

SPSS
SigmaPlot
Living Image

Related Concepts

Related Feeds

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.