title: DACH1 inhibits SNAI1-mediated epithelial-mesenchymal transition and represses breast carcinoma metastasis.
abstract: Epithelial-mesenchymal transition (EMT) has a major role in cancer progression and metastasis. However, the specific mechanism of transcriptional repression involved in this process remains largely unknown. Dachshund homologue 1 (DACH1) expression is lost in invasive breast cancer with poor prognosis, and the role of DACH1 in regulating breast cancer metastasis is poorly understood. In this study, significant correlation between the expression of DACH1 and the morphology of breast cancer cells was observed. Subsequent investigation into the relationship between DACH1 and EMT showed that overexpression of DACH1 in ZR-75-30 cells induced a shift towards epithelial morphology and cell-cell adhesion, as well as increased the expression of the epithelial marker E-cadherin and suppressed cell migration and invasion. In contrast, silencing DACH1 in MCF-7 and T47D cells disrupted the epithelial morphology and cell-cell contact, reduced the expression of E-cadherin, and induced cell migration and invasion. DACH1 also specifically interacted with SNAI1, but not SNAI2, to form a complex, which could bind to the E-box on the E-cadherin promoter in an SNAI1-dependent manner. DACH1 inhibited the transcriptional activity of SNAI1, leading to the activation of E-cadherin in breast cancer cells. Furthermore, the level of DACH1 also correlated with the extent of metastasis in a mouse model. DACH1 overexpression significantly decreased the metastasis and growth of 4T1/Luc cells in BALB/c mice. Analysis of tissue samples taken from human breast cancers showed a significant correlation between the expression of DACH1 and E-cadherin in SNAI1-positive breast cancer. Collectively, our data identified a new mechanistic pathway for the regulation of EMT and metastasis of breast cancer cells, one that is based on the regulation of E-cadherin expression by direct DACH1-SNAI1 interaction.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhao
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: X
authors.initials: X
authors.lastname: Bai
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: H
authors.initials: H
authors.lastname: Bi
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: X
authors.initials: X
authors.lastname: Ao
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Jia
authors.affiliation: 1] School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China [2] School of Life Science and Medicine, Dalian University of Technology, Panjin, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu