title: PATZ1 induces PP4R2 to form a negative feedback loop on IKK/NF-κB signaling in lung cancer.
abstract: 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.
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC.
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Ho
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Liang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC.|Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan, ROC.
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Liang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D025461:Feedback, Physiological / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; C412784:PATZ1 protein, human; D012097:Repressor Proteins; D051550:I-kappa B Kinase; D010749:Phosphoprotein Phosphatases; C080406:protein phosphatase 4
keywords: IκB kinase (IKK); PATZ1; epithelial-mesenchymal transition (EMT); migration/invasion/metastasis; protein phosphatase 4 (PP4)