title: Promoter hypomethylation and upregulation of trefoil factors in prostate cancer.
abstract: Trefoil factors, mucin-associated peptides, are overexpressed in prostate cancer (PC). We hypothesized that promoter methylation contributes to the regulation of trefoil factors (TFF1, TFF2 and TFF3) in human prostate cells. Here we show hypomethylation of promoter regions of TFF1 and TFF3 in PC cell lines with significant TFF expression as compared to benign immortalized prostate cell lines and PC cell lines not expressing trefoil factor. The most striking difference was observed for CpG sites located close to the AUG start codon overlapping several putative binding sites for cellular transcription factors. TFF2 was hypermethylated and had no or very low expression in all prostate cell lines investigated. Treatment of methylated cell lines with 5-aza-2'-deoxycytidine restored TFF expression in cell lines not expressing TFF and increased expression significantly in low-expressing cell lines. In clinical samples, methylation of the promoter/enhancer regions of TFF1 and TFF3 was significantly lower in PC compared to benign prostatic hyperplasia. The present study shows an inverse relation between promoter methylation and expression of trefoil factors. Preliminary analysis on clinical samples suggests that this regulatory mechanism is responsible for the increased levels of TFF1 and TFF3 observed in PC. The overexpression and promoter hypomethylation of trefoil factors may serve as biomarkers in PC.
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital Skejby, Brendstrupgaardsvej, Aarhus N, Denmark. else.marie.vestergaard@dadlnet.dk
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Vestergaard
authors.forename: Ebba
authors.initials: E
authors.lastname: Nexø
authors.forename: Niels
authors.initials: N
authors.lastname: Tørring
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Karina Dalsgaard
authors.initials: KD
authors.lastname: Sørensen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D010455:Peptides / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D010455:Peptides; C051838:TFF1 protein, human; C000604007:TFF2 protein, human; C082495:TFF3 protein, human; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins