title: A novel epigenetic mechanism regulating hyaluronan production in pancreatic cancer cells.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant stroma enriched with hyaluronan (HA), a major component of extracellular matrix known to play a critical role in tumor progression. The mechanisms that regulate HA synthesis in PDAC are poorly understood. To investigate whether DNA methylation and HA production from PDAC cells are associated, we studied the effect of 5-aza-2'-deoxycitidine (5-aza-dC), an inhibitor of DNA methylation, or DNA methyltransferase 1 (DNMT1) knockdown by small interfering RNA, on the HA production from PDAC cells. HA production into the conditioned medium was evaluated in PDAC cells treated with 5-aza-dC or DNMT1 knockdown. mRNA expression of HA synthase (HAS) genes was investigated by real-time RT-PCR. Treatment of PDAC cells with 5-aza-dC led to a significant increase in the HA production (up to 2.5-fold increase) in all 4 cell lines tested. This enhanced HA production by 5-aza-dC treatment was accompanied by increased mRNA expression of HAS2 and HAS3. Furthermore, increased HA production and HAS2/HAS3 mRNA expression was also observed in PDAC cells by knockdown of DNMT1. These findings provide evidence, for the first time, that epigenetic mechanism is involved in the regulation of HA synthesis in PDAC cells.
authors.affiliation: Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Kohi
authors.affiliation: Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan. norisato@med.uoeh-u.ac.jp.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Cheng
authors.affiliation: Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Koga
authors.affiliation: Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
authors.forename: Aiichiro
authors.initials: A
authors.lastname: Higure
authors.affiliation: Department of Surgery 1, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirata
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases
keywords: 5-aza-2′-deoxycytidine; DNA methylation; DNA methyltransferase 1; HAS; Hyaluronan