Table 1.

DNA methylation regulates Keap1-Nrf2 signaling pathway.

Target	Diseases	Methylation	Experimental Model	Impact on Keap1-Nrf2	Outcomes	Ref
Nrf2	Prostate cancer	↑	TRAMP mice and TRAMP-C1 cells	↓ Nrf2, NQO1, GST mu	Prostate carcinogenesis	[40-42]
		↑	Human prostate cancer tissues	↓ Nrf2	Advanced stages	[43]
		↓	TRAMP-C1 or LNCap cells treated by 5-Aza/TSA	↑ Nrf2, NQO1, HO-1 ↓ DNMTs, HDACs	Not Applicable	[42, 43]
		↓	TRAMP-C1 cells or TRAMP mice treated by γ-TmT, curcumin, sulforaphane, 3,3′- diindolylmethane, or Z-Ligustilide	↑ Nrf2, NQO1, HO-1 ↓ DNMT, HDAC	Inhibition of carcinogenesis	[44, 49- 52]
	Skin cancer	↓	Mouse skin epidermal JB6 P+ cells treated by sulforaphane, apigenin, or Tanshinone IIA	↑ Nrf2, NQO1, HO-1 ↓ DNMT, HDAC	Inhibition of TPA-induced transformation	[53-55]
Keap1	Lung cancer	↑	Human lung cancer tissues and cell lines	↓ Keap1	Not Applicable	[56, 57]
			Human non-small cell lung cancer	Not Applicable	Worse prognosis	[58]
	Gliomas	↑	Human malignant gliomas	↓ Keap1	Better prognosis	[59]
	Breast cancer	↑	Primary breast cancers and pre- invasive lesions	↓ Keap1	Higher mortality in triple- negative; reduced relapse	[60]
	Colorectal cancer	↑	Colorectal cancer cell lines and surgical specimens	↓ Keap1 ↑ Nrf2, NQO1, AKR1C1	Not Applicable	[61]
	Prostate cancer	↑	Prostate cancer cell lines	↓ Keap1; ↑ Nrf2, HO-1, NQO1, Gclc	Increased tumor growth, enhanced chemo- and radio-resistance	[63]
	Thyroid cancers	↑	Papillary thyroid carcinoma	↓ Keap1 ↑ Nrf2-regulated genes	Not Applicable	[64]
	Age-related cataracts	↓	Cataractous lenses with increasing age or in diabetes patients; human lens epithelial cells treated by homocysteine, valproic acid, methylglyoxal or selenite	↑ Keap1, TET1 ↓ Nrf2, CAT, GST, DNMT	Elevated ROS, age-related cataracts	[65, 67- 72]
	Diabetic cardiomyopathy	↓	Myocardial biopsies of non- diabetic and type-2 diabetic cardiomyopathy patients	↓ Keap1 ↑ Nrf2-regulated genes	Failure of Nrf2 mediated antioxidant system	[73]