Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Issue 3 (5th December 2011)

• Record Type: Journal Article
• Authors: Aghdassi, Ali; Sendler, Matthias; Guenther, Annett; Mayerle, Julia; Behn, Claas-Olsen; Heidecke, Claus-Dieter; Friess, Helmut; Büchler, Markus; Evert, Matthias; Lerch, Markus M; Weiss, Frank Ulrich
• Is Part Of: Gut. Volume 61:Issue 3(2012)
• Page Start: 439
• Page End: 448
• Publication Date: 2011-12-05
• Subjects: 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 -- ACINI -- acute pancreatitis -- adhesion molecules -- pancreatic surgery -- liver metabolism -- pancreatic enzymes -- pancreatitis -- pancreatic disorders -- chronic pancreatitis -- trypsinogen activation peptide; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2011-300060
• Languages: English
• ISSNs: 0017-5749

Abstract

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.