title: SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c controls epithelial-mesenchymal transition by inducing Wnt5a signaling.
abstract: We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen identified the genes within this 140-gene signature that promoted the conversion of mesenchymal epithelial cell adhesion molecule-negative (EpCAM-) breast cancer cells to an epithelial EpCAM+/high phenotype. The screen identified 10 of the 140 genes whose individual knockdown was sufficient to promote EpCAM and E-cadherin expression. Among these 10 genes, RNAi silencing of the SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c in EpCAM- breast cancer cells gave the most robust transition from the mesenchymal to epithelial phenotype. Conversely, expression of Smarcd3/Baf60c in immortalized human mammary epithelial cells induced an EMT. The mesenchymal-like phenotype promoted by Smarcd3/Baf60c expression resulted in gene expression changes in human mammary epithelial cells similar to that of claudin-low triple-negative breast cancer cells. These mammary epithelial cells expressing Smarcd3/Baf60c had upregulated Wnt5a expression. Inhibition of Wnt5a by either RNAi knockdown or blocking antibody reversed Smarcd3/Baf60c-induced EMT. Thus, Smarcd3/Baf60c epigenetically regulates EMT by activating WNT signaling pathways.
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Nicole Vincent
authors.initials: NV
authors.lastname: Jordan
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.forename: Amy N
authors.initials: AN
authors.lastname: Abell
authors.forename: Jon S
authors.initials: JS
authors.lastname: Zawistowski
authors.forename: Noah
authors.initials: N
authors.lastname: Sciaky
authors.forename: Olga A
authors.initials: OA
authors.lastname: Karginova
authors.forename: Bingying
authors.initials: B
authors.lastname: Zhou
authors.forename: Brian T
authors.initials: BT
authors.lastname: Golitz
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D011518:Proto-Oncogene Proteins; C491649:SMARCD3 protein, human; D014157:Transcription Factors; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein