Abstract
NRF2 is a key focus in cancer research because of its preventive/promotional roles depending on context. While NRF2 is largely activated by posttranslational modifications of thiol residues in its inhibitor KEAP1, additional mechanisms at the transcriptional and posttranscriptional levels participate in the complex regulation of NRF2/KEAP1 pathway. In this regard, epigenetic modifications in NRF2/KEAP1 have emerged as key events regulating NRF2 activity in the preclinical and clinical settings. Such alterations of NRF2/KEAP1 reported in cancer cells include methylation of cytosine residues in DNA, histone acetylation, interaction with BET bromodomain proteins, and regulation by noncoding RNAs (ncRNAs). Therapeutic intervention of these epigenetic alterations, which are reversible in nature, is hypothesized to yield better clinical benefits in cancer. Toward this end, a few epi-drugs including HDAC inhibitors (e.g., valproic acid, vorinostat, phytochemicals), DNMT inhibitors (e.g., 5-aza-cytidine, phytochemicals), and BET inhibitors (e.g., JQ1) have been found to be promising in the preclinical phase. While DNMT inhibitors mostly have been found to reverse promoter methylation of Nfe2l2 and upregulate NRF2 leading to cancer chemoprevention, HDAC and BET inhibitors were reported to downregulate NRF2 causing chemo- or radiosensitization of cancer cells. However, at present, the research on epi-drugs targeting this master regulator of stress-responsive pathway is in rudimentary stage, and further mechanistic studies on existing epi-drugs or identification of novel epigenetic modifiers of NRF2/KEAP1 are warranted for clinical translation of these promising preclinical data. Considering the frequent epigenetic alterations of NRF2 and/or KEAP1 observed in cancer patients, the epigenetic landscape of this pathway provides a promising avenue for therapeutic intervention in cancer.
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Abbreviations
- 3′UTR:
-
3′ untranslated region
- AML:
-
Acute myeloid leukemia
- ARE:
-
Antioxidant response element
- BET:
-
Bromodomain and extraterminal domain
- BETi:
-
BET inhibitors
- CBP :
-
CREB-binding protein
- ccRC:
-
Clear cell renal carcinoma
- ChIP:
-
Chromatin immunoprecipitation
- Cul3:
-
Cullin 3
- DNMT:
-
DNA methyltransferase
- DNMTi:
-
DNMT inhibitors
- ESCC:
-
Esophageal squamous cell carcinoma
- EZH2:
-
Enhancer of zeste homolog 2
- HAT :
-
Histone acetyltransferase
- HDAC:
-
Histone deacetylase
- HDACi:
-
HDAC inhibitors
- HMOX-1:
-
Hemeoxygenase-1
- HOTAIR:
-
Hox transcript antisense intergenic RNA
- KEAP1:
-
Human gene encoding KEAP1 protein
- Keap1:
-
Murine gene encoding KEAP1 protein
- Keap1:
-
Murine Kelch-like ECH-associated protein 1
- lncRNA:
-
Long noncoding RNA
- MALAT1:
-
Metastasis-associated lung adenocarcinoma transcript 1
- MEG3:
-
Maternally expressed gene-3
- miRNA:
-
MicroRNA
- ncRNA:
-
Noncoding RNA
- NFE2L2 :
-
Human gene encoding NRF2 protein
- Nfe2l2 :
-
Murine gene encoding NRF2 protein
- NRAL:
-
NRF2 regulation-associated lncRNA
- NRF2 and KEAP1:
-
The corresponding human proteins
- NRF2:
-
Murine nuclear factor erythroid 2-related factor 2
- NSCLC:
-
Non-small cell lung carcinoma
- PR [C2]:
-
Polycomb repressive complex 2
- RNS:
-
Reactive nitrogen species
- ROS:
-
Reactive oxygen species
- SCF:
-
S-phase kinase-associated protein 1/cullin/F-box
- SETD7/Set7/9:
-
SET domain-containing 7
- Sp1:
-
Specificity protein 1
- TET:
-
Ten-eleven translocation
- TRAMP :
-
Transgenic adenocarcinoma mouse prostate
- TUG1:
-
Taurine-upregulated gene 1
- UCA1:
-
Urothelial carcinoma associated 1
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Bhattacharjee, S. (2022). Epigenetic Regulators of NRF2. In: Chakraborti, S. (eds) Handbook of Oxidative Stress in Cancer: Therapeutic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-16-1247-3_73-1
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