Epigenetic regulation of Keap1-Nrf2 signaling

The kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis serves as a “master regulator” in response to oxidative/electrophilic stresses and chemical insults through the coordinated induction of a wide array of cytoprotective genes. Therefore, activation of Nrf2 is considered to be an important approach for preventing chronic diseases triggered by stresses and toxins, including cancer. Despite extensive studies suggested that the Keap1-Nrf2 signaling pathway is subject to multiple layers of regulation at the transcriptional, translational, and post-translational levels, the potential epigenetic regulation of Nrf2 and Keap1 has begun to be recognized only in recent years. Epigenetic modifications, heritable alterations in gene expression that occur without changes in the primary DNA sequence, have been reported to be profoundly involved in oxidative stress responses. In this review, we discuss the latest findings regarding the epigenetic regulation of Keap1-Nrf2 signaling by DNA methylation, histone modification, and microRNAs. The crosstalk among these epigenetic modifications in the regulation of Keap1-Nrf2 signaling pathways is also discussed. Studies of the epigenetic modification of Nrf2 and Keap1 have not only enhanced our understanding of this complex cellular defense system but have also provided potential new therapeutic targets for the prevention of certain diseases.