Human pancreatic carcinoma cells activate maspin expression through loss of epigenetic control.
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, and 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, and in so doing appear to co-opt a normal cellular mechanism for the regulation of this gene.
Fitzgerald
Matthew
M
Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, Iowa City, IA 52242, USA.
Oshiro
Marc
M
Holtan
Nicholas
N
Krager
Kimberly
K
Cullen
Joseph J
JJ
Futscher
Bernard W
BW
Domann
Frederick E
FE
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D020799:Pancrelipase / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000096:biosynthesis* / Q000378:metabolism; D013447:Sulfites / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D011506:Proteins; D012333:RNA, Messenger; C085344:SERPIN-B5; D015843:Serpins; D013447:Sulfites; D020799:Pancrelipase; D000077209:Decitabine; D003596:Cytosine; D001374:Azacitidine; C009279:sodium bisulfite