PATZ1 induces PP4R2 to form a negative feedback loop on IKK/NF-κB signaling in lung cancer
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Ming-Yi Ho1, Chi-Ming Liang1, Shu-Mei Liang1,2
1Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC
2Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC
Chi-Ming Liang, email: [email protected]
Shu-Mei Liang, email: [email protected]
Keywords: epithelial-mesenchymal transition (EMT), IκB kinase (IKK), migration/invasion/metastasis, PATZ1, protein phosphatase 4 (PP4)
Received: February 29, 2016 Accepted: June 17, 2016 Published: July 6, 2016
Activation of IKK enhances NF-κB signaling to facilitate cancer cell migration, invasion and metastasis. Here, we uncover the existence of a negative feedback loop of IKK. The transcription factor PATZ1 induces protein phosphatase-4 (PP4) regulatory subunit 2 (PP4R2) in an IKK-dependent manner. PP4R2 enhances the binding of PP4 to phosphorylated IKK to inactivate IKK/NF-κB signaling during sustained stimulation by cellular stimuli such as growth factors and inflammatory mediators. Matched pair studies reveal that primary lung cancers express more PATZ1 and PP4R2 than lymph node metastases in patients. Ectopic PATZ1 decreases invasion/colonization of lung cancers and prolongs the survival of xenograft mice. These effects of PATZ1 are reversed by downregulating PP4R2. Our results suggest that PATZ1 and PP4R2 provide negative feedback on IKK/NF-κB signaling to prevent cancer cells from over-stimulation from cellular stimuli; a decline in PATZ1 and PP4R2 is functionally associated with cancer migration/invasion and agents enhancing PATZ1 and PP4R2 are worth exploring to prevent invasion/metastasis of lung cancers.
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