title: Negative feedback loop between p66Shc and ZEB1 regulates fibrotic EMT response in lung cancer cells.
abstract: The epithelial-to-mesenchymal transition (EMT) program is crucial for the epithelial cancer progression and fibrotic diseases. Our previous work has demonstrated that p66Shc, a focal adhesion-associated adaptor protein, is frequently downregulated in lung cancers and its depletion promotes metastasis behavior through anoikis resistance. However, mechanism underlying loss of p66Shc and EMT response is not fully understood. Here, we showed that p66Shc deficiency enhanced the expression of ZEB1, the known mesenchymal transcription factor and consequently increased Vimentin, and decreased epithelial markers of E-cadherin and β-catenin. p66Shc depletion also increased cell invasion and migration. In addition, ChIP and luciferase assays showed that these effects were directly mediated by ZEB1 repression of p66Shc promoter. Thus, our findings define a critical role of p66Shc in the suppression of fibrotic EMT response with a negative feedback loop between p66Shc and ZEB1 in lung epithelial cancer cells.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Laboratory of Epigenetics and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: D
authors.initials: D
authors.lastname: Gao
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Laboratory of Epigenetics and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Engineering, Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: X
authors.initials: X
authors.lastname: Yan
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Laboratory of Epigenetics and Tumorigenesis, Tianjin Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China [3] Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China [4] Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital, Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Immunology, School of Basic Medical Sciences, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China [2] Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital, Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
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