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

Int J Cancer. 2010 Jun 1;126(11):2575-83. doi: 10.1002/ijc.24972.


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.

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / physiopathology
  • Cadherins / deficiency
  • Cadherins / genetics*
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • DNA Primers
  • DNA, Neoplasm / genetics
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylases / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness / genetics*
  • Phenotype
  • Promoter Regions, Genetic
  • RNA, Neoplasm / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription, Genetic*
  • Transfection
  • Tumor Cells, Cultured
  • Zinc Finger E-box-Binding Homeobox 1


  • Cadherins
  • DNA Primers
  • DNA, Neoplasm
  • Homeodomain Proteins
  • MicroRNAs
  • RNA, Neoplasm
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Histone Deacetylases