Review Article
Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs
Table 3
Effect of KEAP1/NRF2 expression by promoter methylation in human cancers (tissues and cell lines) and correlation with clinical patients’ outcomes.
| | Molecular target | Cancer model | Methylation status | Functional effects | Clinical outcome | Refs |
| | NRF2 | Prostate cancer cell line (LNCaP) and tissues () | Hypermethylation | ↓ NRF2 mRNA
↓ HO-1 mRNA and protein
↓ NQO1 mRNA and protein | Increment of Gleason score from normal to advanced stage prostate cancer | [121] | | Human colon cancer cells (SNU-C5) | Hypomethylation | ↑ NRF2 mRNA
↑ HO-1 mRNA and protein | NA | [59, 60] |
| | KEAP1 | Lung cancer cell lines (SPC-A1, A549, and NCI-H460) and tissues () | Hypermethylation | ↓ KEAP1 mRNA
↑ NRF2 protein
↑ HO-1 mRNA and protein
↑ GSH mRNA and protein | NA | [48,116, 122] | | NSCLC tissues () | Hypermethylation | ↓ KEAP1 mRNA | Worst prognosis associated to KEAP1 double alterations | [52] | | Malignant gliomas () | Hypermethylation | ↓ KEAP1 mRNA | Lowest risk to progress in patients treated with radiotherapy and temozolomide | [51] | | Primary breast cancers () and preinvasive breast lesions () | Hypermethylation | ↓ KEAP1 mRNA | Worse prognosis in triple-negative phenotype and reduced risk of relapse in patients treated with EC/D chemotherapy | [53] | | Human colorectal cancer cell lines () and tissues () | Hypermethylation | ↓ KEAP1 mRNA
↑ NRF2 protein
↑ NQO1 mRNA
↑ AKR1C1 mRNA | NA | [55] | | Prostate cancer cell DU-145 | Hypermethylation | ↓ KEAP1 mRNA
↑ NRF2 mRNA
↑ NQO1 mRNA
↑ HO-1 mRNA
↑ GCLC mRNA | NA | [49] | ccRCC tissues ()
TCGA dataset () | Hypermethylation | ↓ KEAP1 mRNA | Worse overall survival (OS) and association with increased of tumor grading | [54] |
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AKR1C1: aldo-keto reductase family 1 member C1; ccRCC: clear renal cell carcinoma; GCLC: glutamate-cysteine ligase catalytic subunit; GSH: glutathione; HO-1: heme oxygenase-1; KEAP1: Kelch-like ECH-associated protein 1; NQO1: NAD(P)H-quinone oxidoreductase 1; NRF2: nuclear factor erythroid 2-related factor 2; NSCLC: non-small-cell lung cancer; NA: not applicable.
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