title: Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer.
abstract: OBJECTIVE
  Pancreatic cancer is characterised by invasive tumour spread and early metastasis formation. During epithelial-mesenchymal transition, loss of the cell adhesion molecule E-cadherin is frequent and can be caused by genetic or epigenetic modifications, recruitment of transcriptional activators/repressors or post-translational modifications. A study was undertaken to investigate how E-cadherin expression in human pancreatic adenocarcinoma and pancreatic cancer cell lines is regulated.
  
  
  METHODS
  In 25 human pancreatic cancer resection specimens, the coding region of the E-cadherin gene (CDH1) was sequenced for somatic mutations. The tumour samples and 11 established human pancreatic cancer cell lines were analysed by immunohistochemistry, western blot analysis, chromatin immunoprecipitation and methylation-specific PCR. The role of specific histone deacetylase inhibitors (HDACi) on pancreatic tumour cell migration and proliferation was studied in vitro.
  
  
  RESULTS
  Neither somatic mutations nor CDH1 promoter hypermethylation were found to be responsible for downregulation of E-cadherin in pancreatic cancer. In the transcriptionally active CDH1 promoter, acetylation of histones H3 and H4 was detected whereas HDAC1 and HDAC2 were found attached only to a silent promoter. Expression of ZEB1, a transcription factor known to recruit HDACs, was seen in E-cadherin-deficient cell lines in which ZEB1/HDAC complexes were found attached to the CDH1 promoter. Moreover, knockdown of ZEB1 prevented HDAC from binding to the CDH1 promoter, resulting in histone acetylation and expression of E-cadherin. HDACi treatment attenuated tumour cell migration and proliferation.
  
  
  CONCLUSIONS
  These findings imply an important role for histone deacetylation in the downregulation of E-cadherin in human pancreatic cancer. Recruitment of HDACs to the CDH1 promoter is regulated by the transcription factor ZEB1, and inhibition of HDACs may be a promising antitumour therapy for pancreatic cancer.
authors.affiliation: Department of Medicine A, Ernst-Moritz-Arndt Universität Greifswald, Friedrich-Loefler-Str. 23a, 17475 Greifswald, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Aghdassi
authors.forename: Matthias
authors.initials: M
authors.lastname: Sendler
authors.forename: Annett
authors.initials: A
authors.lastname: Guenther
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Claas-Olsen
authors.initials: CO
authors.lastname: Behn
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Heidecke
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Markus
authors.initials: M
authors.lastname: Büchler
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Weiss
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000502:physiology*; D056464:Histone Deacetylase 2 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2