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.
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA.
Volodymyr P
VP
Tryndyak
Frederick A
FA
Beland
Igor P
IP
Pogribny
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D015820:Cadherins / Q000172:deficiency / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012334:RNA, Neoplasm / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D017931:DNA Primers; D004273:DNA, Neoplasm; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012334:RNA, Neoplasm; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D006655:Histone Deacetylases