Integrin Alpha 6 Beta 4 Upregulates Amphiregulin And Epiregulin Through Base Excision Repairmediated Dna Demethylation And Promotes Genome-Wide Dna Hypomethylation

Aberrant DNA methylation patterns are a common theme across all cancer types. Specific DNA demethylation of regulatory sequences can result in upregulation of genes that are critical for tumor development and progression. Integrin alpha 6 beta 4 is highly expressed in pancreatic carcinoma and contributes to cancer progression, in part, through the specific DNA demethylation and upregulation of epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG). Whole genome bisulfite sequencing (WGBS) revealed that integrin alpha 6 beta 4 signaling promotes an overall hypomethylated state and site specific DNA demethylation of enhancer elements within the proximal promoters of AREG and EREG. Additionally, we find that the base excision repair (BER) pathway is required to maintain expression of AREG and EREG, as blocking DNA repair molecules, TET1 GADD45A, TDG, or PARP-1 decreased gene expression. Likewise, we provide the novel finding that integrin alpha 6 beta 4 confers an enhanced ability on cells to repair DNA lesions and survive insult. Therefore, while many known signaling functions mediated by integrin alpha 6 beta 4 that promote invasive properties have been established, this study demonstrates that integrin alpha 6 beta 4 can dramatically impact the epigenome of cancer cells, direct global DNA methylation levels toward a hypomethylated state, and impact DNA repair and subsequent cell survival.