title: Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression.
abstract: Slug (Snail2) plays critical roles in regulating the epithelial-mesenchymal transition (EMT) programs operative during development and disease. However, the means by which Slug activity is controlled remain unclear. Herein we identify an unrecognized canonical Wnt/GSK3β/β-Trcp1 axis that controls Slug activity. In the absence of Wnt signaling, Slug is phosphorylated by GSK3β and subsequently undergoes β-Trcp1-dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3β kinase activity is inhibited, nuclear Slug levels increase, and EMT programs are initiated. Consistent with recent studies describing correlative associations in basal-like breast cancers between Wnt signaling, increased Slug levels, and reduced expression of the tumor suppressor Breast Cancer 1, Early Onset (BRCA1), further studies demonstrate that Slug-as well as Snail-directly represses BRCA1 expression by recruiting the chromatin-demethylase, LSD1, and binding to a series of E-boxes located within the BRCA1 promoter. Consonant with these findings, nuclear Slug and Snail expression are increased in association with BRCA1 repression in a cohort of triple-negative breast cancer patients. Together, these findings establish unique functional links between canonical Wnt signaling, Slug expression, EMT, and BRCA1 regulation.
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Zhao-Qiu
authors.initials: ZQ
authors.lastname: Wu
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Li
authors.forename: Casey Yuexian
authors.initials: CY
authors.lastname: Hu
authors.forename: Michael
authors.initials: M
authors.lastname: Ford
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008745:Methylation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D060449:Wnt Signaling Pathway
chemical_list: D019313:BRCA1 Protein; D006657:Histones; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3