Inhibition of epithelial to mesenchymal transition by E-cadherin up-regulation via repression of slug transcription and inhibition of E-cadherin degradation: dual role of scaffold/matrix attachment region-binding protein 1 (SMAR1) in breast cancer cells

• Published in: The Journal of biological chemistry Vol. 289; no. 37; pp. 25431 - 25444
• Main Authors: Adhikary, Arghya, Chakraborty, Samik, Mazumdar, Minakshi, Ghosh, Swatilekha, Mukherjee, Shravanti, Manna, Argha, Mohanty, Suchismita, Nakka, Kiran Kumar, Joshi, Shruti, De, Abhijit, Chattopadhyay, Samit, Sa, Gaurisankar, Das, Tanya
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 12.09.2014
• Subjects: Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cadherins - biosynthesis; Cadherins - genetics; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Movement - genetics; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Humans; Molecular Bases of Disease; Neoplasm Metastasis; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proteolysis; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Snail Family Transcription Factors; Transcription Factors - genetics; E3 Ubiquitin Ligase; Metastasis; Cadherin-1 (CDH1) (Epithelial Cadherin) (E-cadherin); Migration; Epithelial-Mesenchymal Transition (EMT)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.527267

The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. It has been acknowledged that aberrant activation of a latent embryonic program, known as the epithelial-mesenchymal transition (EMT), can endow cancer cells with the migratory and invasive capabilities associated with metastatic competence for which E-cadherin switch is a well-established hallmark. Discerning the molecular mechanisms that regulate E-cadherin expression is therefore critical for understanding tumor invasiveness and metastasis. Here we report that SMAR1 overexpression inhibits EMT and decelerates the migratory potential of breast cancer cells by up-regulating E-cadherin in a bidirectional manner. While SMAR1-dependent transcriptional repression of Slug by direct recruitment of SMAR1/HDAC1 complex to the matrix attachment region site present in the Slug promoter restores E-cadherin expression, SMAR1 also hinders E-cadherin-MDM2 interaction thereby reducing ubiquitination and degradation of E-cadherin protein. Consistently, siRNA knockdown of SMAR1 expression in these breast cancer cells results in a coordinative action of Slug-mediated repression of E-cadherin transcription, as well as degradation of E-cadherin protein through MDM2, up-regulating breast cancer cell migration. These results indicate a crucial role for SMAR1 in restraining breast cancer cell migration and suggest the candidature of this scaffold matrix-associated region-binding protein as a tumor suppressor.