title: Specificity protein 1 (Sp1) maintains basal epithelial expression of the miR-200 family: implications for epithelial-mesenchymal transition.
abstract: Epithelial-mesenchymal transition (EMT) is required for the specification of tissues during embryonic development and is recapitulated during the metastatic progression of tumors. The miR-200 family plays a critical role in enforcing the epithelial state with their expression lost in cells undergoing EMT. EMT can be mediated by activation of the ZEB1 and ZEB2 (ZEB) transcription factors, which repress miR-200 expression via a self-reinforcing double negative feedback loop to promote the mesenchymal state. However, it remains unclear what factors drive and maintain epithelial-specific expression of miR-200 in the absence of EMT-inducing factors. Here, we show that the transcription factor Specificity Protein 1 (Sp1) binds to the miR-200b∼200a∼429 proximal promoter and activates miR-200 expression in epithelial cells. In mesenchymal cells, Sp1 expression is maintained, but its ability to activate the miR-200 promoter is perturbed by ZEB-mediated repression. Reduction of Sp1 expression caused changes in EMT-associated markers in epithelial cells. Furthermore, we observed co-expression of Sp1 and miR-200 during mouse embryonic development wherein miR-200 expression was only lost in regions with high ZEB expression. Together, these findings indicate that miR-200 family members require Sp1 to drive basal expression and to maintain an epithelial state.
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kolesnikoff
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia,; Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia, and.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Attema
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Suraya
authors.initials: S
authors.lastname: Roslan
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bert
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Quenten P
authors.initials: QP
authors.lastname: Schwarz
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia,; Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia, and. Electronic address: philip.gregory@health.sa.gov.au.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.affiliation: Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia 5000, Australia,; Discipline of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia, and; School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: greg.goodall@health.sa.gov.au.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: Epithelial mesenchymal transition; Metastasis; MicroRNA; Sp1; Transcription; ZEB transcription factor; miR-200