title: Suppression of the epithelial-mesenchymal transition by Grainyhead-like-2.
abstract: Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-β receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cieply
authors.forename: Philip
authors.initials: P
authors.lastname: Riley
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Pifer
authors.forename: Joseph
authors.initials: J
authors.lastname: Widmeyer
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Addison
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ivanov
authors.forename: James
authors.initials: J
authors.lastname: Denvir
authors.forename: Steven M
authors.initials: SM
authors.lastname: Frisch
mesh_terms: D023102:Anoikis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1