title: Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer.
abstract: Expression of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), is often lost due to promoter DNA methylation in basal-like breast cancer (BLBC), which contributes to the metastatic advantage of this disease; however, the underlying mechanism remains unclear. Here, we identified that Snail interacted with Suv39H1 (suppressor of variegation 3-9 homolog 1), a major methyltransferase responsible for H3K9me3 that intimately links to DNA methylation. We demonstrated that the SNAG domain of Snail and the SET domain of Suv39H1 were required for their mutual interactions. We found that H3K9me3 and DNA methylation on the E-cadherin promoter were higher in BLBC cell lines. We showed that Snail interacted with Suv39H1 and recruited it to the E-cadherin promoter for transcriptional repression. Knockdown of Suv39H1 restored E-cadherin expression by blocking H3K9me3 and DNA methylation and resulted in the inhibition of cell migration, invasion and metastasis of BLBC. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT, but also paves a way for the development of new treatment strategies against this disease.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The University of Kentucky College of Medicine, Lexington, KY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Dong
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Kang
authors.forename: P G
authors.initials: PG
authors.lastname: Rychahou
authors.forename: Y-I
authors.initials: YI
authors.lastname: Chi
authors.forename: B M
authors.initials: BM
authors.lastname: Evers
authors.forename: B P
authors.initials: BP
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D063185:Epigenetic Repression / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008958:Models, Molecular; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D015820:Cadherins; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C407843:SUV39H1 protein, human; D008780:Methyltransferases