Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs

Abstract

Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 (Kelch-like erythroid-derived cap-n-collar homology- (ECH-) associated protein-1/nuclear factor (erythroid-derived 2)-like 2) axis. The physical interaction between these two proteins promotes the expression of several antioxidant defense genes in response to exogenous and endogenous insults. Recent studies demonstrated that KEAP1/NRF2 axis dysfunction is also strongly related to tumor progression and chemo- and radiotherapy resistance of cancer cells. In solid tumors, the KEAP1/NRF2 system is constitutively activated by the loss of KEAP1 or gain of NFE2L2 functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes. In addition to point mutations, epigenetic abnormalities, as aberrant promoter methylation, and microRNA (miRNA) and long noncoding RNA (lncRNA) deregulation were reported as emerging mechanisms of KEAP1/NRF2 axis modulation. This review will summarize the current knowledge about the epigenetic mechanisms that deregulate the KEAP1/NRF2 cascade in solid tumors and their potential usefulness as prognostic and predictive molecular markers.

Figure 1

Overview of the main genetic and epigenetic modifications that lead to KEAP1-NFE2L2 impairment and constitutive NRF2 nuclear accumulation in cancer cells. NFE2L2 gene copy number variations (CNV), oncogene activity (KRAS, BRAF, MYC, and PTEN), DNA promoter methylation, and miRNAs contribute in a synergic manner to increase cancerous NRF2 activity as a result of reduction of KEAP1 mRNA or increase of NRF2 mRNA levels and/or protein expression. By contrast, somatic point gain-of-function mutations in NFE2L2 or in loss-of-function in KEAP1 promote the disruption of the interaction between KEAP1 and NRF2 and lead the increase of NRF2 protein quantity which translocates into the nucleus.

Figure 2

Domain architecture of the NRF2 (a) and KEAP1 (b) proteins. (a) NRF2 protein is divided into seven highly conserved domains, Neh1 to Neh7 (NRF2-ECH homology: Neh). The coordinates of NRF2 protein domains are shown as follows: Neh2 (16-89aa); Neh2 DLG motif (17-32aa), Neh2 ETGE motif (77-82aa), Neh4 (111-134aa), Neh5 (182-209aa), Neh7 (209-316aa), Neh6 (337-394aa), Neh1 (435-568aa), and Neh3 (569-605aa). (b) KEAP1 protein contains a number of functional domains including the N-terminal region (NTR; 1-60aa), broad complex, tramtrack and bric-a-brac (BTB; 61-179aa), the intervening linker domain (IVR; 180-314aa), the double glycine/Kelch domain harboring six Kelch-repeat domains (315-359aa; 361-410aa; 412-457aa; 459-504aa; 506-551aa; 553-598aa), and the C-terminal region (CTR; 599-624aa).

Figure 3

Left and right panels show how miRNA modifications may contribute to down and upregulate the KEAP1/NRF2 signaling in cancer. Representative scheme on the left side summarizes a group of miRNAs that directly target KEAP1 mRNA and indirectly impact on the transcriptional activity of the NRF2 into the nucleus. Other miRNAs modulate BACH1, a transcription factor that competes with NRF2 leading to the link at the antioxidant response element (ARE) of detoxifying genes. The schematic model on the right side depicts those miRNAs that directly target NFE2L2 and impact on the general mRNA and protein levels of NRF2 and, by consequence, on the activation of detoxification NRF2 target genes with a great impact on chemo- and radioresistance, survival, growth, and proliferation of tumor cells.