title: Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer.
abstract: BACKGROUND
  DNA hypermethylation is proved to be involved in carcinogenesis. Because chronic pancreatitis (CP) is a consistent risk factor for pancreatic cancer, the possible alteration and tumor contribute effects of hypermethylated in cancer-1 (HIC1) promoter methylation in CP was investigated.
  
  
  METHODS
  Methylation of HIC1 promoter HIC1 and SIRT1 expression were detected in human normal pancreas (NP), CP and pancreatic adenocarcinoma tissues. Furthermore, HIC1/SIRT1 pathway was regulated by demethylating reagent and exogenous expression in PANC-1, BxPC-3 and AsPC-1 cell lines, cell biology behavior including proliferation, apoptosis, cell cycle and senescence were detected.
  
  
  RESULTS
  The methylation of HIC1 promoter was demonstrated in 70.3 % pancreatic carcinoma (45 of 64), 47.5 % CP (19 of 40) and 11.4 % NP tissues (4 of 35). Moreover, hypermethylation of HIC1 promoter and deregulation of HIC1 expression in pancreatic cancer were significantly related to high-stage tumor and older patient age. HIC1 promoter hypermethylation was also observed in pancreatic cancer cell lines including PANC-1, BxPC-3 and AsPC-1. Restoration of HIC1 function with 5-aza-dC treatment or pCDNA3FlagHIC1 plasmid transfection leaded to a reduction in cell proliferation, obvious cell senescence, cell cycle arrest and apoptosis, accompanied with acetylated p53 and p21(WAF1 of Cip1) upregulation. While after further transfected with pCDNA3FlagSIRT1 plasmid, the growth inhibition, senescence and cycle arrest without apoptosis were partially rescued with deregulated acetylated p53 and p21(WAF1 of Cip1).
  
  
  CONCLUSIONS
  Our results indicate that hypermethylation of HIC1 promoter in CP may contribute to the aberrant expression of HIC1/SIRT1 pathway and then involve in the pancreatic carcinogenesis.
authors.affiliation: Pancreatic Disease Institute, Union Hospital, Wuhan City, Hubei Province, China, zhaogang1427@gmail.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Qi
authors.initials: Q
authors.lastname: Qin
authors.forename: Jungang
authors.initials: J
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Shichang
authors.initials: S
authors.lastname: Deng
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Kui
authors.initials: K
authors.lastname: Tian
authors.forename: Chunyou
authors.initials: C
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D004247:DNA; C447939:SIRT1 protein, human; D056564:Sirtuin 1