title: Regulation of thrombomodulin expression in prostate cancer cells.
abstract: In carcinomas the expression of thrombomodulin (TM) is inversely correlated with tumour progression and metastasis. In the present study a decreased TM expression in human prostate cancer cell lines, LNCaP, DU-145, and PC-3, in relation to normal prostate epithelial cells (PrEC) is shown. Sequencing and methylation-specific high resolution melting (MS-HRM) analyses of bisulphite-modified genomic DNA indicates a high degree of methylation in DU-145 cells and lesser degrees in PC-3 and LNCaP cells, whereas in PrEC the TM promoter is unmethylated. The expression of TM is negatively regulated by NF-κB- and GSK3-β-dependent signalling pathways and positively regulated by retinoic acid and transcription factor Sp1 in PrEC, LNCaP and PC-3 cells, but not in DU-145 cells. However, exposure of DU-145 cells to the demethylating agent, 5-aza-2'deoxycytidine, restores the TM expression and its control by retinoic acid, NF-κB- and GSK3-β-dependent signalling. In conclusion, the study establishes that in prostate cancer cell lines relative to PrEC the TM is down-regulated and that the TM promoter is hypermethylated, which seems to be responsible for the down-regulation and failed regulation of TM expression in DU-145 cells.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Technical University of Dresden, Medical Faculty "Carl Gustav Carus", Germany. Mario.Menschikowski@uniklinikum-dresden.de
authors.forename: Mario
authors.initials: M
authors.lastname: Menschikowski
authors.forename: Albert
authors.initials: A
authors.lastname: Hagelgans
authors.forename: Oliver
authors.initials: O
authors.lastname: Tiebel
authors.forename: Margot
authors.initials: M
authors.lastname: Vogel
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siegert
mesh_terms: D002460:Cell Line; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D018180:Thrombomodulin; D014212:Tretinoin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3