Integrin α6β4 regulates promoter demethylation of EGFR ligands

Abstract

Pancreatic cancer is the 4th leading cause of cancer death in the US due to late detection and lack of effective treatments. The integrin α6β4 is overexpressed in most pancreatic adenocarcinomas where it contributes to tumor invasion. We find that integrin α6β4 overexpression leads to upregulation of amphiregulin and epiregulin, ligands of the epidermal growth factor receptor. The purpose of this study is to address how integrin α6β4 upregulates these ligands. Pancreatic cancer cells expressing low levels of α6β4 were treated with DNA methyltransferase inhibitor 5‐aza‐2′deoxycitidine. Using Q‐PCR, our results show that inhibition of DNA methyltransferase increases amphiregulin and epiregulin expression at the mRNA level. In contrast, when cells with high levels of integrin α6β4 were treated with the hypermethylating agent, S‐adenosylmethionine, it leads to a decrease in amphiregulin and epiregulin expression. Using ELISA, we also provide evidence that integrin α6β4 promotes increased autocrine secretion of amphiregulin after promoter demethylation. This study indicates that overexpression of integrin α6β4 in pancreatic cancer is associated with the hypomethylation of amphiregulin and epiregulin promoters, which may play an important role in the development of malignancy. This study was supported by the Markey Cancer Center.