Article Text

Download PDFPDF
Original article
Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer
  1. Ali Aghdassi1,
  2. Matthias Sendler1,
  3. Annett Guenther1,
  4. Julia Mayerle1,
  5. Claas-Olsen Behn1,
  6. Claus-Dieter Heidecke2,
  7. Helmut Friess3,
  8. Markus Büchler4,
  9. Matthias Evert5,
  10. Markus M Lerch1,
  11. Frank Ulrich Weiss1
  1. 1Department of Medicine A, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
  2. 2Department of Surgery, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
  3. 3Department of Surgery, Technical University Munich, Munich, Germany
  4. 4Department of Surgery, University of Heidelberg, Heidelberg, Germany
  5. 5Institute of Pathology, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
  1. Correspondence to Professor Markus M Lerch, Department of Medicine A, Ernst-Moritz-Arndt Universität Greifswald, Friedrich-Loefler-Str. 23a, 17475 Greifswald; lerch{at}


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.

  • Cancer genetics
  • epithelial cell adhesion
  • pancreatic cancer
  • E-cadherin
  • RNA expression
  • tumour markers
  • epigenetics
  • liver cirrhosis
  • molecular oncology
  • pancreatic tumours
  • pancreatic disease
  • pancreatic pseudocyst
  • cadherins
  • acute pancreatitis
  • adhesion molecules
  • pancreatic surgery
  • liver metabolism
  • pancreatic enzymes
  • pancreatitis
  • pancreatic disorders
  • chronic pancreatitis
  • trypsinogen activation peptide

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • See Commentary, p 329

  • Linked articles 301576.

  • Funding This study was supported by grants from the Alfried-Krupp-von-Bohlen-und-Hahlbach-Foundation (Graduate Schools Tumour Biology and Free Radical Biology), University Medicine Greifswald (Forschungsverbund Molekulare Medizin), the Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung (102031-Le and 109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-E3/E4, MA 4115/1-2/3, LE 625/8-1 and 9-1), the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107) and the European Union (EU-FP-7: EPC-TM No. 256974 and EU-FP7-REGPOT-2010-1). AA was supported by a Gerhard-Domagk-Stipendium of Greifswald University.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the local ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Linked Articles