Abstract
Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human NFE2L2/KEAP1 and murine Nfe2l2/Keap1 genes, acetylation of lysine residues in NRF2 and Nrf2, interaction with bromodomain and extraterminal domain (BET) acetyl “reader” proteins, and non-coding RNAs such as microRNA (miRNA) and long non-coding RNA (lncRNA). Phytochemicals documented to modulate NRF2 signaling act by reversing hypermethylated states in the CpG islands of NFE2L2 or Nfe2l2, via the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), through the induction of ten-eleven translocation (TET) enzymes, or by inducing miRNA to target the 3′-UTR of the corresponding mRNA transcripts. To date, fewer than twenty phytochemicals have been reported as NRF2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. This opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target NRF2 signaling with a view to beneficial interception of cancer and other chronic diseases.
Highlights
The NRF2 signaling axis has received widespread attention from the research community due to its critical role in responding to xenobiotic and electrophilic stress [1]
Non-coding RNAs linked to NRF2 signaling include miRNAs, which contain ~22 nucleotides, and long non-coding RNA (lncRNA), which are greater than 200 nucleotides in length
Other work in HepG2 cells treated with high glucose and in high-fat models of non-alcoholic fatty liver disease (NAFLD) found that the methylation status of the NFE2L2 gene was increased, while that of KEAP1 was decreased, leading to decreased NRF2 expression and activity [91]
Summary
The NRF2 signaling axis has received widespread attention from the research community due to its critical role in responding to xenobiotic and electrophilic stress [1]. Inactivating mutations in KEAP1 that lead to constitutive NRF2 activation [5,6] can provide a growth advantage in some cancer cells. In view of this functional duality, NRF2 has been discussed both as a “friend or foe” or a “double-edged sword” in cancer etiology [10,11]. Genetic alterations initially were reported in NFE2L2/KEAP1, more recently, epigenetic mechanisms have added a new dimension and an element of fine-tuning to the NRF2 signaling axis. The present review aims to provide an update on the various phytochemicals that regulate NRF2 via the “epigenetic trinity” of DNA methylation, histone modifications, and non-coding RNAs
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