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 SMAR1 in breast cancer cells [Cell Biology]

August 1st, 2014 by Adhikary, A., Chakraborty, S., Mazumdar, M., Ghosh, S., Mukherjee, S., Manna, A., Mohanty, S., Nakka, K. K., Joshi, S., De, A., Chattopadhyay, S., Sa, G., Das, T.

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 over-expression 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, upregulating 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.
  • Posted in Journal of Biological Chemistry, Publications
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