Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs.
Federico Pio FabrizioA SparaneoD TrombettaLucia Anna MuscarellaPublished in: Oxidative medicine and cellular longevity (2018)
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.
Keyphrases
- oxidative stress
- dna methylation
- genome wide
- protein protein
- long noncoding rna
- induced apoptosis
- gene expression
- nuclear factor
- poor prognosis
- healthcare
- toll like receptor
- physical activity
- early stage
- transcription factor
- long non coding rna
- radiation therapy
- mental health
- signaling pathway
- risk assessment
- locally advanced
- anti inflammatory
- squamous cell carcinoma
- drug delivery
- copy number
- rectal cancer
- binding protein
- cell cycle arrest