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.
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 humanpancreatic adenocarcinoma and pancreatic cancer cell lines is regulated. METHODS: In 25 humanpancreatic cancer resection specimens, the coding region of the E-cadherin gene (CDH1) was sequenced for somatic mutations. The tumour samples and 11 established humanpancreatic 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 humanpancreatic 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: Ser Yue Loo; Jayshree L Hirpara; Vijay Pandey; Tuan Zea Tan; Celestial T Yap; Peter E Lobie; Jean Paul Thiery; Boon Cher Goh; Shazib Pervaiz; Marie-Véronique Clément; Alan Prem Kumar Journal: Antioxid Redox Signal Date: 2016-08-20 Impact factor: 8.401
Authors: Lyndsay V Rhodes; Chandra R Tate; H Chris Segar; Hope E Burks; Theresa B Phamduy; Van Hoang; Steven Elliott; Diari Gilliam; F Nell Pounder; Muralidharan Anbalagan; Douglas B Chrisey; Brian G Rowan; Matthew E Burow; Bridgette M Collins-Burow Journal: Breast Cancer Res Treat Date: 2014-05-09 Impact factor: 4.872
Authors: Angela L McCleary-Wheeler; Gwen A Lomberk; Frank U Weiss; Günter Schneider; Muller Fabbri; Tara L Poshusta; Nelson J Dusetti; Sandra Baumgart; Juan L Iovanna; Volker Ellenrieder; Raul Urrutia; Martin E Fernandez-Zapico Journal: Cancer Lett Date: 2012-10-13 Impact factor: 8.679