Introduction The dismal prognosis of pancreatic cancer due to the delayed diagnosis, rapid metastasis and resistance to current therapeutics, signifies the importance of identifying novel therapeutic approaches. Although the past two decades of research have focused on identifying genetic alterations, in the recent years it has become apparent that pancreatic cancer is as much a disease of DNA mutations as it is a disease of misregulated epigenetics.
Method We analysed alterations at the epigenomic (genome-wide DNA methylation), transcriptomic (gene expression) and miRNomic (miRNA expression) level, in 20 pancreatic cancer and 14 normal tissues. We then performed data integration through the Starburst analysis and explored for overlapping changes in DNA methylation and gene expression. To validate our data, gene expression was further studied through real time RT-PCR and immunohistochemistry. To elucidate the clinical significance of our findings, we conducted immunohistochemistry in a tissue microarray containing 154 tissue specimens from pancreatic cancer and matched non-neoplastic tissue samples. To address the functional importance and characterise the pathways involved, we performed a series of cell-based pancreatic cancer assays.
Results This analysis revealed hepatocyte nuclear factor 4A (HNF4A), a key transcription factor in the development and proper function of the pancreas, as a novel target for aberrant DNA methylation. Hypermethylation is identified in several loci of the HNF4A gene promoter and there is a positive correlation between HNF4A hypermethylation and down-regulation in pancreatic cancer tissues. Our preliminary data indicate the activity of an epigenetic feedback circuit that involves HNF4A, microRNAs and DNA methyltransferases (DNMTs). Clinicopathological analysis revealed that low HNF4A expression correlates with poor survival. Our functional studies indicate that the HNF4A-circuit acts as a tumour suppressor, regulating pancreatic cancer growth, invasiveness and chemoresistance.
Conclusion Our data suggest that the HNF4A-miRNA-DNMTs molecular network plays a central role in pancreatic cancer progression and its perturbation holds promise as a novel therapeutic approach.
Disclosure of Interest None Declared
- pancreatic cancer therapy
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