PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-κB- and HDAC1-mediated expression and activation of uPA.

Abstract

Although protein kinase D3 (PKD3) has been shown to contribute to prostate cancer cell growth and survival, the role of PKD in prostate cancer cell motility remains unclear. Here, we show that PKD2 and PKD3 promote nuclear factor kappa B (NF-κB) signaling and urokinase-type plasminogen activator (uPA) expression/activation, which are crucial for prostate cancer cell invasion. Silencing of endogenous PKD2 and/or PKD3 markedly decreased prostate cancer cell migration and invasion, reduced uPA and uPA receptor (uPAR) expression and increased plasminogen activator inhibitor-2 (PAI-2) expression. These results were further substantiated by the finding that PKD2 and PKD3 promoted the activity of uPA and matrix metalloproteinase 9 (MMP9). Furthermore, depletion of PKD2 and/or PKD3 decreased the level of binding of the p65 subunit of NF-κB to the promoter of the gene encoding uPA (PLAU), suppressing transcriptional activation of uPA. Endogenous PKD2 and PKD3 interacted with inhibitor of NF-κB (IκB) kinase β (IKKβ); PKD2 mainly regulated the phosphorylated IKK (pIKK)-phosphorylated IκB (pIκB)-IκB degradation cascade, p65 nuclear translocation, and phosphorylation of Ser276 on p65, whereas PKD3 was responsible for the phosphorylation of Ser536 on p65. Conversely, inhibition of uPA transactivation by PKD3 silencing was rescued by constitutive Ser536 p65 phosphorylation, and reduced tumor cell invasion resulting from PKD2 or PKD3 silencing was rescued by ectopic expression of p65. Interestingly, PKD3 interacted with histone deacetylase 1 (HDAC1), suppressing HDAC1 expression and decreasing its binding to the uPA promoter. Moreover, depletion of HDAC1 resulted in recovery of uPA transactivation in PKD3-knockdown cells. Taken together, these data suggest that PKD2 and PKD3 coordinate to promote prostate cancer cell invasion through p65 NF-κB- and HDAC1-mediated expression and activation of uPA.

• Authors: Zhipeng Zou, Fangyin Zeng, Wanfu Xu, Chunxia Wang, Zhiyong Ke, Q Jane Wang, Fan Deng
• Journal: Journal of cell science (J Cell Sci) Vol. 125 Issue Pt 20 Pg. 4800-11 (Oct 15 2012) ISSN: 1477-9137 [Electronic] England
• PMID: 22797919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TRPP Cation Channels
• Transcription Factor RelA
• polycystic kidney disease 2 protein
• protein kinase C nu
• Protein Kinase C
• Urokinase-Type Plasminogen Activator
• MMP9 protein, human
• Matrix Metalloproteinase 9
• HDAC1 protein, human
• Histone Deacetylase 1

Topics

• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase 1 (genetics, metabolism)
• Humans
• Male
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Neoplasm Invasiveness
• Phosphorylation
• Prostatic Neoplasms (genetics, metabolism)
• Protein Kinase C (genetics, metabolism)
• Signal Transduction
• TRPP Cation Channels (genetics, metabolism)
• Transcription Factor RelA (genetics, metabolism)
• Transcriptional Activation (genetics)
• Urokinase-Type Plasminogen Activator (genetics, metabolism)