E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells.

The conversion of early stage tumors into invasive malignancies with an aggressive phenotype has been associated with the irreversible loss of E-cadherin expression. The loss of E-cadherin expression in human tumors, including breast cancer, has been attributed to promoter CpG island hypermethylation and direct inhibition by transcriptional repressors. Recent evidence demonstrates that up-regulation of E-cadherin by microRNA-200b (miR-200b) and miR-200c through direct targeting of transcriptional repressors of E-cadherin, ZEB1, and ZEB2, inhibits epithelial-to-mesenchymal transition (EMT), a crucial process in the tumor progression. We demonstrate that microRNA miR-200 family-mediated transcriptional up-regulation of E-cadherin in mesenchymal MDA-MB-231 and BT-549 cells is associated directly with translational repression of ZEB1 and indirectly with increased acetylation of histone H3 at the E-cadherin promoter. The increase in histone H3 acetylation may be attributed to the disruption of repressive complexes between ZEB1 and histone deacetylases and to the inhibition of SIRT1, a class III histone deacetylase. These events inhibit EMT and reactivate a less aggressive epithelial phenotype in cancer cells. Additionally, disruption of ZEB1-histone deacetylase repressor complexes and down-regulation of SIRT1 histone deacetylase up-regulate proapoptotic genes in the p53 apoptotic pathway resulting in the increased sensitivity of cancer cells to the chemotherapeutic agent doxorubicin.