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J Biol Chem. 2014 Sep 12;289(37):25431-44. doi: 10.1074/jbc.M113.527267. Epub 2014 Aug 1.

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.

Author information

1
From the Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700 054, India.
2
the National Centre for Cell Science (NCCS), Pune University Campus, Ganeshkhind, Pune 411007, India, and.
3
the Molecular Functional Imaging Laboratory, Tata Memorial Centre, ACTREC, Navi, Mumbai, Maharastra 410210, India.
4
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.

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.

KEYWORDS:

Cadherin-1 (CDH1) (Epithelial Cadherin) (E-cadherin); E3 Ubiquitin Ligase; Epithelial-Mesenchymal Transition (EMT); Metastasis; Migration

PMID:
25086032
PMCID:
PMC4162148
DOI:
10.1074/jbc.M113.527267
[Indexed for MEDLINE]
Free PMC Article

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