RESUMO
Plakophilin 3 (PKP3) belongs to the p120ctn family of armadillo-related proteins predominantly functioning in desmosome formation. Here we report that PKP3 is transcriptionally repressed by the E-cadherin repressor ZEB1 in metastatic cancer cells. ZEB1 physically associates with two conserved E-box elements in the PKP3 promoter and partially represses the activity of corresponding human and mouse PKP3 promoter fragments in reporter gene assays. In human tumours ZEB1 is upregulated in invasive cancer cells at the tumour-host interface, which is accompanied by downregulation of PKP3 expression levels. Hence, the transcriptional repression of PKP3 by ZEB1 contributes to ZEB1-mediated disintegration of intercellular adhesion and epithelial to mesenchymal transition.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neoplasias/patologia , Placofilinas/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Caderinas/metabolismo , Progressão da Doença , Proteínas de Homeodomínio/análise , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Invasividade Neoplásica , Neoplasias/química , Neoplasias/genética , Placofilinas/análise , Regiões Promotoras Genéticas , Proteínas Repressoras/análise , Proteínas Repressoras/genética , Fatores de Transcrição/análise , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Homeobox 1 de Ligação a E-box em Dedo de ZincoRESUMO
Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal transition (EMT) in embryonic development and cancer progression. Using the EpFosER mammary tumour model we show that during EMT, upregulation of the transcriptional regulator deltaEF1 coincided with transcriptional repression of E-cadherin. Ectopic expression of deltaEF1 in epithelial cells was sufficient to downregulate E-cadherin and to induce EMT. Analysis of E-cadherin promoter activity and chromatin immunoprecipitation identified deltaEF1 as direct transcriptional repressor of E-cadherin. In human cancer cells, transcript levels of deltaEF1 correlated directly with the extent of E-cadherin repression and loss of the epithelial phenotype. The protein was enriched in nuclei of human cancer cells and physically associated with the E-cadherin promoter. RNA interference-mediated downregulation of deltaEF1 in cancer cells was sufficient to derepress E-cadherin expression and restore cell to cell adhesion, suggesting that deltaEF1 is a key player in late stage carcinogenesis.
