title: 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.
abstract: 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.
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Samik
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Minakshi
authors.initials: M
authors.lastname: Mazumdar
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Swatilekha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Shravanti
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Argha
authors.initials: A
authors.lastname: Manna
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: the National Centre for Cell Science (NCCS), Pune University Campus, Ganeshkhind, Pune 411007, India, and.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Nakka
authors.affiliation: the National Centre for Cell Science (NCCS), Pune University Campus, Ganeshkhind, Pune 411007, India, and.
authors.forename: Shruti
authors.initials: S
authors.lastname: Joshi
authors.affiliation: the Molecular Functional Imaging Laboratory, Tata Memorial Centre, ACTREC, Navi, Mumbai, Maharastra 410210, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: De
authors.affiliation: the National Centre for Cell Science (NCCS), Pune University Campus, Ganeshkhind, Pune 411007, India, and.
authors.forename: Samit
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
authors.affiliation: From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India, tanya@jcbose.ac.in.
authors.forename: Tanya
authors.initials: T
authors.lastname: Das
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics
chemical_list: C417914:BANP protein, human; D015820:Cadherins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: Cadherin-1 (CDH1) (Epithelial Cadherin) (E-cadherin); E3 Ubiquitin Ligase; Epithelial-Mesenchymal Transition (EMT); Metastasis; Migration
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