Hypermethylation of HIC1 Promoter and Aberrant Expression of HIC1/SIRT1 Might Contribute to the Carcinogenesis of Pancreatic Cancer
- 508 Downloads
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.
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.
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 p21WAF1 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 p21WAF1 of Cip1.
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.
KeywordsPancreatic Cancer Chronic Pancreatitis Pancreatic Cancer Cell Pancreatic Cancer Cell Line Normal Pancreas
This work was supported by a grant from the National Natural Science Foundation of China (grants 30600594 and 30972900) and the Fundamental Research Funds for the Central Universities of China (grant 2011JC046).
Conflict of interest
All authors have no competing interest to declare.
- 18.Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual, Sixth Edition. New York: Springer-Verlag. 2010.Google Scholar
- 31.Kim EJ, Um SJ. SIRT1: roles in aging and cancer. Biochem Mol Biol Rep. 2008;41:751–6.Google Scholar