Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression.
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.
Pubmed ID: 23011797 RIS Download
Amino Acid Sequence | BRCA1 Protein | Blotting, Western | Breast Neoplasms | Cell Line, Tumor | Epigenesis, Genetic | Epithelial-Mesenchymal Transition | Gene Expression Regulation, Neoplastic | Glycogen Synthase Kinase 3 | Glycogen Synthase Kinase 3 beta | HEK293 Cells | Histone Demethylases | Histones | Humans | Immunohistochemistry | MCF-7 Cells | Methylation | Molecular Sequence Data | Phosphorylation | Reverse Transcriptase Polymerase Chain Reaction | Sequence Homology, Amino Acid | Snail Family Transcription Factors | Transcription Factors | Ubiquitination | Wnt Signaling Pathway