Epigenetic Silencing of GNMT Gene in Pancreatic Adenocarcinoma

Abstract

Background/aim: Although pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for therapy, biomarkers for early detection are lacking. Epigenetic silencing of tumor suppressor genes is a majorcontributor to neoplastic transformation. The aim of this study was to identify new factors involved in PDAC progression. The GNMT gene possesses CpG islands in the promoter region and is important in methyl-group metabolism and in maintaining a normal methylation status of the genome.

Materials and methods: To test the hypothesis whether GNMT is epigenetically regulated in PDAC, we evaluated the GNMT gene expression and promoter methylation status in 30 paired samples of PDAC and normal pancreatic tissue.

Results: We found significantly higher methylation frequencies (p<0.001) in PDACs (2.82-100%; median, 36.05%) than in controls (0.28-14.02%; median, 4.39%). The GNMT gene expression was decreased in PDACs compared to normal pancreatic tissues in 26/30 cases (86.67%). Furthermore, we showed that treatment with 5-aza-2-deoxycytidine (5-aza-dC) increased GNMT mRNA expression and decreased viability in PDAC cells.

Conclusion: Collectively, these data indicate that GNMT is aberrantly methylated in PDAC representing, thus, a potential major mechanism for gene silencing. Methylation of GNMT gene is directly correlated with disease stage and with tumor grade indicating that these epigenetic effects may be important regulators of PDAC progression.

Keywords: Epigenetic alteration; pancreatic cancer; promoter methylation.