title: Loss of the polycomb protein Mel-18 enhances the epithelial-mesenchymal transition by ZEB1 and ZEB2 expression through the downregulation of miR-205 in breast cancer.
abstract: The epithelial-mesenchymal transition (EMT) is the pivotal mechanism underlying the initiation of cancer invasion and metastasis. Although Mel-18 has been implicated in several biological processes in cancer, its function in the EMT of human cancers has not yet been studied. Here, we demonstrate that Mel-18 negatively regulates the EMT by epigenetically modulating miR-205. We identified miR-205 as a novel target of Mel-18 using a microRNA microarray analysis and found that Mel-18 increased miR-205 transcription by the inhibition of DNA methyltransferase-mediated DNA methylation of the miR-205 promoter, thereby downregulating its target genes, ZEB1 and ZEB2. Furthermore, the loss of Mel-18 promoted ZEB1- and ZEB2-mediated downregulation of E-cadherin transcription and also enhanced the expression of mesenchymal markers, leading to increased migration and invasion in MCF-7 cells. In MDA-MB-231 cells, Mel-18 overexpression restored E-cadherin expression, resulting in reduced migration and invasion. These effects were reversed by miR-205 overexpression or inhibition. A tumor xenograft with Mel-18 knockdown MCF-7 cells consistently showed increased ZEB1 and ZEB2 expression and decreased E-cadherin expression. Taken together, these results suggest that Mel-18 functions as a tumor suppressor by its novel negative control of the EMT, achieved through regulating the expression of miR-205 and its target genes, ZEB1 and ZEB2.
authors.affiliation: Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Dongguk University, Seoul, Korea.
authors.forename: M K
authors.initials: MK
authors.lastname: Park
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Park
authors.affiliation: College of Pharmacy, Dongguk University, Seoul, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Dongguk University, Seoul, Korea.
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.affiliation: 1] Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea [2] Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: G
authors.initials: G
authors.lastname: Kong
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D063150:Polycomb Repressive Complex 1 / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D063150:Polycomb Repressive Complex 1; D012097:Repressor Proteins; D014157:Transcription Factors; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C513384:CDH1 protein, human; C534425:MIR205, human; C489348:PCGF2 protein, human; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human