Human Pancreatic Carcinoma Cells Activate Maspin Expression Through Loss of Epigenetic Control

Neoplasia: An International Journal for Oncology Research

Nicholas Holtan¹  Marc Oshiro¹  Bernard W. Futscher¹  Matthew Fitzgerald²  Kimberly Krager²  Frederick E. Domann²  Joseph J. Cullen³ 

[1] Department of Pharmacology and Toxicology, Bone Marrow Transplant Program, Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA;Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242, USA;Department of Surgery, University of Iowa, Iowa City, IA 52242, USA;

关键词: histone acetylation;    DNA methylation;    tumor suppressor gene;    cancer;    gene expression;   

DOI  :  10.1016/S1476-5586(03)80045-3

来源: DOAJ

【 摘 要 】

The maspin gene is not expressed in normal human pancreas, but its expression is acquired during human pancreatic carcinogenesis. In other normal human cells and their malignant counterparts, maspin expression is controlled through the epigenetic state of its promoter. In studies presented herein, we used bisulfite genomic sequencing and chromatin immunoprecipitation studies to show that maspin-negative pancreas cells have a methylated maspin promoter, that the associated H3 and H4 histones are hypoacetylated. In contrast to normal pancreas, four of six human pancreatic carcinoma cell lines investigated displayed activation of maspin expression. This activation of maspin expression in pancreatic carcinoma cells was linked to demethylated promoters and hyperacetylation of the associated H3 and H4 histones. In addition, 5-aza-2′-deoxycytidine treatments activated maspin expression in the two maspin-negative pancreatic carcinoma cell lines, suggesting a causal role for cytosine methylation in the maintenance of a transcriptionally silent maspin gene. Thus, human pancreatic carcinoma cells acquire maspin expression through epigenetic derepression of the maspin locus, in so doing appear to co-opt a normal cellular mechanism for the regulation of this gene.

【 授权许可】

Unknown