While our knowledge of cancer epigenetics has developed rapidly, how dynamic epigenetic regulation is influenced by the tumor microenvironment to foster a metastasis phenotype has yet to be revealed. We find that integrin α6β4 is a critical mediator of DNA demethylation of two pro-invasive molecules, AREG and EREG. These specific changes in DNA demethylation of AREG and EREG occurred at enhancer elements within their proximal promoters that drive their expression downstream of integrin α6β4. Similarly, our data support integrin α6β4 as a modulator of genome-wide DNA methylation patterns, as overexpression of integrin α6β4 resulted in dramatic hypomethylation of the genome, with a significant percentage of these CpGs located in putative enhancer sites. Lastly, our study revealed that integrin α6β4 not only utilizes the BER DNA repair but also facilitates enhanced repair of DNA lesions, as cells with high integrin α6β4 survived better in response to oxidative stress, and directly repaired 6-4 photoproducts more rapidly. Our unique findings provide evidence that places integrin α6β4 as a critical mediator of cancer epigenetics, and thus offer new mechanisms for the integrin’s role in cancer progression.