title: ZEB2-Sp1 cooperation induces invasion by upregulating cadherin-11 and integrin α5 expression.
abstract: Epithelial-mesenchymal transition (EMT) is a process implicated in invasion and metastasis. EMT is characterized by repression of epithelial markers and induction of mesenchymal markers. ZEB2 is a transcriptional repressor of E-cadherin, leading to EMT. Previously, we have shown that ZEB2 directly upregulates integrin α5 transcription by cooperating with the transcription factor Sp1. In this study, we investigated the precise mechanism by which ZEB2 modulates invasion and EMT events and the role of Sp1 in ZEB2-induced invasion. We found that ZEB2 directly induced cadherin-11 transcription in an Sp1-dependent, but Smad- and E-box-independent, manner and repressed E-cadherin expression in an Sp1- and Smad-independent manner, leading to cadherin switch. Furthermore, ZEB2 upregulated Sp1 by enhancing Sp1 protein stability, and Sp1 was found to be critical for ZEB2-induced cancer cell invasion, mainly through induction of cadherin-11 and integrin α5. Expression levels of cadherin-11 and integrin α5 were interdependent and both modulated c-Jun N-terminal kinase-signaling activity and invasion. Immunofluorescence analysis showed that nuclear expression of ZEB2 was positively correlated with Sp1 expression in human colorectal cancers. Together, these findings demonstrate a previously unrecognized interplay between ZEB2, Sp1, cadherin-11 and integrin α5 that is, probably, significant in tumor progression and metastasis.
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-806, Korea.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Nam
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Lee
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Zhao
authors.forename: Young-Kyu
authors.initials: YK
authors.lastname: Park
authors.forename: Jung Weon
authors.initials: JW
authors.lastname: Lee
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D039482:Integrin alpha5; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; C086960:osteoblast cadherin