Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

Abstract

Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis. NRF2 function is well studied in in vitro, animal and general physiology models. However, emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer, autism, anxiety disorders and diabetes. A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes. The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species (ROS) neutralizing and cytoprotective drug-metabolizing enzymes (phase I, II, III and 0). Further, NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance. Interestingly, we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome. This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes, which extends beyond its described classical role as a ROS regulator. This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner. This places NRF2 as a key determinant of action, effectiveness and resistance to anticancer therapy.

Keywords

Cancer / nuclear factor E2-related factor 2 / drug resistance / receptor tyrosine kinase inhibitor / DNA damage and repair response / targeted therapy / anticancer therapeutics

References

[1] Housman GHeerboth SLongacre MDrug resistance in cancer: an overview..Cancers (Basel)2014;6:1769-92PMC4190567

[2] Lage HAn overview of cancer multidrug resistance: a still unsolved problem..Cell Mol Life Sci2008;65:3145-67

[3] Hu XUnderstanding the Genetic Mechanisms of Cancer Drug Resistance Using Genomic Approaches..Trends Genet2016;32:127-37

[4] Fojo TStrategies for reversing drug resistance..Oncogene2003;22:7512-23

[5] Gottesman MMBates SEMultidrug resistance in cancer: role of ATP-dependent transporters..Nat Rev Cancer2002;2:48-58

[6] Longley DBMolecular mechanisms of drug resistance..J Pathol2005;205:275-92

[7] Debatin KMDeath receptors in chemotherapy and cancer..Oncogene2004;23:2950-66

[8] Swanton CIntratumor heterogeneity: evolution through space and time..Cancer Res2012;72:4875-82PMC3712191

[9] Taylor STDive CEpigenetic determinants of resistance to etoposide regulation of Bcl-X(L) and Bax by tumor microenvironmental factors..J Natl Cancer Inst2000;92:18-23

[10] Valent PDe Maria RCopland MCancer stem cell definitions and terminology: the devil is in the details..Nat Rev Cancer2012;12:767-75

[11] Lee TITranscriptional regulation and its misregulation in disease..Cell2013;152:1237-51PMC3640494

[12] Hanahan DHallmarks of Cancer: The Next Generation..Cell2011;144:646-74

[13] Kohno KNiina IIgarashi TTranscription factors and drug resistance..Eur J Cancer2005;41:2577-86

[14] Zou WYang HChen BHepatitis B X-interacting protein promotes cisplatin resistance and regulates CD147 via Sp1 in ovarian cancer..Exp Biol Med2017;242:497-504PMC5367657

[15] Uchida YTaguchi YUmehara HCeramide Reduction and Transcriptional Up-Regulation of Glucosylceramide Synthase through Doxorubicin-Activated Sp1 in Drug-Resistant HL-60/ADR Cells..Cancer Res2004;64:6271-9

[16] Mo DNiu KWu MHuman Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT-YB1-MDR1 Signaling Pathway..Cancer Res2016;76:3057-66

[17] Yan XYZhang JJLiu YNp62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1-NF-κB pathway in human ovarian cancer cells..Cancer Sci2017;108:1405-13PMC5497928

[18] Bao LDodson MNing YABCF2, an Nrf2 target gene, contributes to cisplatin resistance in ovarian cancer cells..Mol Carcinog2017;56:1543-53PMC5509336

[19] Shibata TGotoh MOhta TGenetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer..Gastroenterology2008;135:1358-68, 68 e1-4

[20] Jiang TZhao FKong BHigh levels of Nrf2 determine chemoresistance in type II endometrial cancer..Cancer Res2010;70:5486-96PMC2896449

[21] Ren DJiang TLau ABrusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism..Proc Natl Acad Sci U S A2011;108:1433-8PMC3029730

[22] Xiang YHuang CChen HBrusatol Enhances the Chemotherapy Efficacy of Gemcitabine in Pancreatic Cancer via the Nrf2 Signalling Pathway..Oxid Med Cell Longev2018;2018:2360427PMC5932458

[23] Wang XJVilleneuve NFZhao FNrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2..Carcinogenesis2008;29:1235-43PMC3312612

[24] Tarumoto TOhmine KNakamura MAscorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line..Exp Hematol2004;32:375-81

[25] Kim SKKim MRKim HGIncreased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells..Free Radic Biol Med2008;45:537-46

[26] Khalil HSGoltsov AHarrison DJA novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells..Oncotarget2016;7:75874-901PMC5342785

[27] Kankia IHLangdon SPBown JLNRF2 Regulates HER1 Signaling Pathway to Modulate the Sensitivity of Ovarian Cancer Cells to Lapatinib and Erlotinib..Oxid Med Cell Longev2017;2017:1864578PMC5749283

[28] Park SHKo EPark MJResistance to gefitinib and cross-resistance to irreversible EGFR-TKIs mediated by disruption of the Keap1-Nrf2 pathway in human lung cancer cells..FASEB J2018;[Epub ahead of print]

[29] Pei SD’Alessandro AStevens BMRational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells..J Biol Chem2016;291:21984-2000PMC5063982

[30] Nawijn MCBerns AFor better or for worse: the role of Pim oncogenes in tumorigenesis..Nat Rev Cancer2011;11:23-34

[31] Li BChen PLi YThe Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma..J Biol Chem2015;290:29854-68PMC4705994

[32] Shiozawa KSoda HIkegami YReversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic..Int J Cancer2004;108:146-51

[33] Robey RWNishiyama KMiyake KOverexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells..Clin Cancer Res2001;7:145-52

[34] Nagashima SOka MShiozawa KBCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer..Cancer Chemother Pharmacol2006;58:594-600

[35] Bai XHou XJin JEmerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters..Drug Metab Rev2016;48:541-67

[36] Chen FZhong CWang XBaicalein reverses hypoxia-induced 5-FU resistance in gastric cancer AGS cells through suppression of glycolysis and the PTEN/Akt/HIF-1alpha signaling pathway..Oncol Rep2015;33:457-63

[37] Leone ACiardiello CVitagliano CVorinostat synergizes with EGFR inhibitors in NSCLC cells by increasing ROS via up-regulation of the major mitochondrial porin VDAC1 and modulation of the c-Myc-NRF2-KEAP1 pathway..Free Radical Bio Med2015;89:287-99

[38] Li MLiu NMeng FSilencing of ATF2 inhibits growth of pancreatic cancer cells and enhances sensitivity to chemotherapy..Cell Biol Int2017;41:599-610

[39] Wakasugi TUchiumi TArao TZNF143 interacts with p73 and is involved in cisplatin resistance through the transcriptional regulation of DNA repair genes..Oncogene2007;26:5194

[40] Mohler JDeutsch EControl of Drosophila head segment identity by the bZIP homeotic gene cnc..Development1995;121:237-47

[41] Chan JYKan YWIsolation of cDNA encoding the human NF-E2 protein..Proc Natl Acad Sci U S A1993;90:11366-70PMC47983

[42] Chan JYKan YWCloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast..Proc Natl Acad Sci U S A1993;90:11371-5PMC47984

[43] Moi PAsunis IKan YWIsolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region..Proc Natl Acad Sci U S A1994;91:9926-30PMC44930

[44] Itoh KHayashi NYamamoto MCloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins..Mol Cell Biol1995;15:4184-93PMC230657

[45] Kobayashi AToki TTakahashi SMolecular cloning and functional characterization of a new Cap’n’collar family transcription factor Nrf3..J Biol Chem1999;274:6443-52

[46] Oyake TMotohashi HHoshino HBach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site..Mol Cell Biol1996;16:6083-95PMC231611

[47] Muto AMadisen LObinata MIdentification of Bach2 as a B-cell-specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3ʹ enhancer..EMBO J1998;17:5734-43PMC1170901

[48] Igarashi KItoh KNishizawa MRegulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins..Nature1994;367:568-72

[49] Igarashi KMuto ANishikawa SMultivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for β-globin locus control region complex..J Biol Chem1998;273:11783-90

[50] Itoh KAn Nrf2/small Maf heterodimer mediates the induction of Phase II detoxifying enzyme genes through antioxidant response elements..Biochem Biophys Res Commun1997;236:313-22

[51] Hayes JDSharma RSDinkova-Kostova ATRegulation of the CNC-bZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-TrCP..Curr Opin Toxicolog2016;1:92-103

[52] O’Mealey GBPlafker SMSulforaphane is a Nrf2-independent inhibitor of mitochondrial fission..Redox Biology2017;11:103-10PMC5126150

[53] Ahmed SMUNamani ATang XNrf2 signaling pathway: Pivotal roles in inflammation..Biochim Biophys Acta Mol Basis Dis2017;1863:585-97

[54] Namani AWang XJModulation of NRF2 signaling pathway by nuclear receptors: Implications for cancer..Biochim Biophys Acta2014;1843:1875-85

[55] Wang XJHenderson CJIdentification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha..Proc Natl Acad Sci U S A2007;104:19589-94PMC2148333

[56] Hayes AJHaugk BKeap1-Nrf2 signalling in pancreatic cancer..Int J Biochem Cell Biol2015;65:288-99

[57] Hayes JDThe Nrf2 regulatory network provides an interface between redox and intermediary metabolism..Trends Biochem Sci2014;39:199-218

[58] McMahon MMacLeod AKHenderson CJHDAC Inhibitors Increase NRF2-Signaling in Tumour Cells and Blunt the Efficacy of Co-Adminstered Cytotoxic Agents..PLoS ONE2014;9:e114055PMC4245243

[59] Hayes JDChowdhry SCancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway..Antioxid Redox Signal2010;13:1713-48

[60] Krajka-Kuźniak VBaer-Dubowska WThe Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment..Pharmacol Rep2017;69:393-402

[61] Huang HCPickett CBRegulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2..Proc Natl Acad Sci U S A2000;97:12475-80PMC18788

[62] Nguyen THuang HCPickett CBIncreased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element Degradation of Nrf2 by the 26 S proteasome..J Biol Chem2003;278:4536-41

[63] Ma QRole of nrf2 in oxidative stress and toxicity..Annu Rev Pharmacol Toxicol2013;53:401-26PMC4680839

[64] Hayes John DNrf2 Orchestrates Fuel Partitioning for Cell Proliferation..Cell Metab2012;16:139-41

[65] Hayes JDThe Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin..Biochem Soc Trans2000;28:33-41

[66] Krajka-Kuźniak VBaer-Dubowska WThe Nrf2-ARE signaling pathway: an update on its regulation and possible role in cancer prevention and treatment..Pharmacol Rep2016;

[67] Xiang MWu SNrf2: bane or blessing in cancer?.J Cancer Res Clin Oncol2014;140:1251-9

[68] Cullinan SBPERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress..J Biol Chem2004;279:20108-17

[69] Lewis KNHayes JDNrf2, a guardian of healthspan and gatekeeper of species longevity..Integr Comp Biol2010;50:829-43PMC2965188

[70] Bruns DRBiela LMMiller BFNrf2 Signaling and the Slowed Aging Phenotype: Evidence from Long-Lived Models..Oxid Med Cell Longev2015;2015:732596PMC4637130

[71] Singh SPSaini DZimniak LDisruption of the mGsta4 gene increases life span of C57BL mice..J Gerontol A Biol Sci Med Sci2010;65:14-23PMC2796882

[72] Sykiotis GPKeap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila..Dev Cell2008;14:76-85PMC2257869

[73] Praslicka BJOoi AThe complex role of NRF2 in cancer: A genomic view..Curr Opin Toxicolog2016;1:37-45

[74] Ramos-Gomez MDolan PMYamamoto MSensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice..Proc Natl Acad Sci U S A2001;98:3410-5PMC30667

[75] Pearson KJPrice NLPerez ENrf2 mediates cancer protection but not prolongevity induced by caloric restriction..Proc Natl Acad Sci U S A2008;105:2325-30PMC2268135

[76] Padmanabhan BOhta TScharlock MStructural Basis for Defects of Keap1 Activity Provoked by Its Point Mutations in Lung Cancer..Mol Cell2006;21:689-700

[77] Singh ADysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer..PLoS Med2006;3:e420PMC1584412

[78] Solis LMDong WOzburn NCNrf2 and Keap1 Abnormalities in Non-Small Cell Lung Carcinoma and Association with Clinicopathologic Features..Clin Cancer Res2010;16:3743-53PMC2920733

[79] Lignitto LHomer HAskenazi MNrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1..Cell2019;178:316-29e18PMC6625921

[80] Wu JTang XRexinoid inhibits Nrf2-mediated transcription through retinoid X receptor alpha..Biochem Biophys Res Commun2014;452:554-9

[81] Chorley BNWang XSambandan DIdentification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha..Nucleic Acids Res2012;40:7416-29PMC3424561

[82] Khalil HSKankia IHDeeni YYNRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted Immunotherapies..Oxid Med Cell Longev2016;PMC4685121

[83] Khalil HNRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response..BioDiscovery2015;15:1

[84] Khalil HSGoltsov AHarrison DJA novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells..Oncotarget2016;7:75874-901PMC5342785

[85] Hayes JDNRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer..Trends Biochem Sci2009;34:176-88

[86] Yen WCPrudente RYBissonnette RPA Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non-Small Cell Lung Cancer..Clin Cancer Res2004;10:8656-64

[87] Yen WCLamph WWSynergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma..Breast Cancer Res Tr2004;88:141-8

[88] Yen WCA selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced prostate cancer..Prostate2006;66:305-16

[89] Olayanju ABryan HKSison RLBrusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity—implications for therapeutic targeting of Nrf2..Free Radical Bio Med2015;78:202-12PMC4291150

[90] Ren DJiang TLau ABrusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism..Proc Natl Acad Sci U S A2011;108:1433-8PMC3029730

[91] Chian SChi ZTang XLuteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo..Biochem Biophys Res Commun2014;447:602-8

[92] Tang XFan LXin ALuteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs..Free Radical Bio Med2011;50:1599-609

[93] Gao AMShi FChen HChrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway..Chem Biol Interact2013;206:100-8

[94] Gao AMWang JNChen SYApigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway..Carcinogenesis2013;34:1806-14

[95] Grossman RThe Dark Side of Nrf2..World Neurosurg2013;80:284-6

[96] Na HKJung JHHyun JW(−)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells..Arch Biochem Biophys2008;476:171-7

[97] Kim SKKim MRKim HGIncreased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells..Free Radical Bio Med2008;45:537-46

[98] Li WLiu TBlank VHeterodimerization with small Maf proteins enhances nuclear retention of Nrf2 via masking the NESzip motif..Biochim Biophys Acta2008;1783:1847-56PMC2570698

[99] Kim SJShim SHAnthocyanins accelerate the healing of naproxen-induced gastric ulcer in rats by activating antioxidant enzymes via modulation of Nrf2..J Funct Foods2014;7:569-79

[100] Kim IUltraviolet radiation-induced non-melanoma skin cancer: Regulation of DNA damage repair and inflammation..Genes Dis2014;1:188-98PMC4307792

[101] Thimmulappa RKSrisuma SYamamoto MIdentification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray..Cancer Res2002;62:5196-203

[102] Kwak MKYamamoto MEnhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter..Mol Cell Biol2002;22:2883-92PMC133753

[103] Lee JSNrf2 as a novel molecular target for chemoprevention..Cancer lett2005;224:171-84

[104] Yu XNrf2 as a target for cancer chemoprevention..Mutat Res2005;591:93-102

[105] Kensler TWNrf2: friend or foe for chemoprevention?.Carcinogenesis2010;31:90-9PMC2802668

[106] Sarkar FHNutraceuticals and Cancer:Springer Science & Business Media;2011;

[107] Ahn YHLiu HZhang YElectrophilic tuning of the chemoprotective natural product sulforaphane..Proc Natl Acad Sci U S A2010;107:9590-5PMC2906893

[108] Talalay PHealy ZRBenedict ALSulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation..Proc Natl Acad Sci U S A2007;104:17500-5PMC2077285

[109] Dietz BMLiu GYao PXanthohumol isolated from Humulus lupulus inhibits menadione-induced DNA damage through induction of quinone reductase..Chem Res Toxicol2005;18:1296-305

[110] Lee ISGal JKim HJAnti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells..Neurochem Int2011;58:153-60

[111] Balogun EPengfei GGreen CJCurcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element..Biochem J2003;371:887-95PMC1223348

[112] Farombi EONa HKSurh YJCurcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1..Food Chem Toxicol2008;46:1279-87

[113] Rushworth SACharalambos CARole of protein kinase C δ in curcumin-induced antioxidant response element-mediated gene expression in human monocytes..Biochem Biophys Res Commun2006;341:1007-16

[114] Clarke JDHo EMulti-targeted prevention of cancer by sulforaphane..Cancer lett2008;269:291-304PMC2579766

[115] Iida KNrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis..Cancer Res2004;64:6424-31

[116] Stefanson ALDietary regulation of Keap1/Nrf2/ARE pathway: focus on plant-derived compounds and trace minerals..Nutrients2014;6:3777-801PMC4179188

[117] Jones RMDarby TMWolfarth AALactobacilli Modulate Epithelial Cytoprotection through the Nrf2 Pathway..Cell Rep2015;12:1217-25PMC4640184

[118] Hamada TMilner DAOgino SIntegration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms..J Pathol2019;247:615-28PMC6509405

[119] Shuji OTsuyoshi HReiko NInsights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology..Annu Rev Pathol-Mech2019;14:83-103PMC6345592

[120] Kwak MKItoh KYamamoto MModulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway Identification of novel gene clusters for cell survival..J Biol Chem2003;278:8135-45

[121] Cho JMLee HRKwak MKRole of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: Implication to cancer cell resistance..Cancer Lett2008;260:96-108

[122] Wang XJNrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2..Carcinogenesis2008;29:1235-43PMC3312612

[123] Goldstein Leonard DGnad FSchaub ARecurrent Loss of NFE2L2 Exon 2 Is a Mechanism for Nrf2 Pathway Activation in Human Cancers..Cell Rep2016;16:2605-17

[124] Wu QLi NDeng YNrf2 mediates redox adaptation in NOX4-overexpressed non-small cell lung cancer cells..Exp Cell Res2017;352:245-54

[125] Tsuchida KHayashi MKeleku-Lukwete NHalofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation..Free Radical Bio Med2017;103:236-47

[126] Kim SKLee DHKim TReversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells..PLoS One2013;8:e78130PMC3806801

[127] Sporn MBNRF2 and cancer: the good, the bad and the importance of context..Nat Rev Cancer2012;12:564-71PMC3836441

[128] Ryoo IGKwak MKInhibitory role of the KEAP1-NRF2 pathway in TGFβ1-stimulated renal epithelial transition to fibroblastic cells: a modulatory effect on SMAD signaling..PloS one2014;9:e93265PMC3972195

[129] Ooi APetillo DPerrier-Trudova VAn Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma..Cancer Cell2011;20:511-23

[130] DeNicola GMMullarky EHu ZNRF2 regulates serine biosynthesis in non-small cell lung cancer..Nat Genet2015;47:1475-81PMC4721512

[131] Ishikawa TGenetic polymorphism in the NRF2 gene as a prognosis marker for cancer chemotherapy..Front Genet2014;5:383PMC4219421

[132] Hartikainen JMKosma VMMannermaa AGenetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer..Cancer Res2012;72:5537-46

[133] Cho HYGladwell WMcCaw ZRAssociation of Nrf2 polymorphism haplotypes with acute lung injury phenotypes in inbred strains of mice..Antioxid Redox Signal2015;22:325-38PMC4298158

[134] Ge WWang XYu MiASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding..Cancer Cell2017;32:561-73.e6

[135] Lau AZhao FWu TA noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62..Mol Cell Biol2010;30:3275-85PMC2897585

[136] Chen WWang XJHuang ZDirect interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response..Mol Cell2009;34:663-73PMC2714804

[137] Wang BKim YHuang SHistone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage..Free RadicaL Bio Med2012;52:928-36PMC6010182

[138] Ji LGao PZhang DDNrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer..PLoS One2013;8:e63404PMC3646742

[139] Dinkova-Kostova ATNAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector..Arch Biochem Biophys2010;501:116-23PMC2930038

[140] Zhong YSun ZLi ZYDrug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response..Mol Carcinogen2013;52:824-34

[141] Hou XGou XXia C3’,4’,5’,5,7-pentamethoxyflavone sensitizes Cisplatin-resistant A549 cells to Cisplatin by inhibition of Nrf2 pathway..Mol Cells2015;38:396-401PMC4443280

[142] Duong HQKang HJTang WInhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine..Int J Oncol2013;44:959-69PMC3928470

[143] Chian SWang XJLuteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway..Asian Pac J Cancer Prev2014;15:2911-6

[144] Beall HDMechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development..Front Biosci2000;5:D639-48

[145] Zhu ZQi CXi GCYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro..Int J Mol Med2015;35:340-8PMC4292762

[146] Rochat BMurray GIMcLeod HLHuman CYP1B1 and Anticancer Agent Metabolism: Mechanism for Tumor-Specific Drug Inactivation?.J Pharmacol Exp Ther2001;296:537-41

[147] Nebert DWMiller WLHuman cytochromes P450 in health and disease..Philos Trans R Soc Lond B Biol Sci2013;368:20120431PMC3538421

[148] McFadyen MCEJackson FCDoehmer JCytochrome P450 CYP1B1 protein expression:: A novel mechanism of anticancer drug resistance11Abbreviations: CYP, cytochrome P450; ANF, alpha-naphthoflavone; MTT, 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide; and 5-FU, 5-fluorouracil..Biochem Pharmacol2001;62:207-12

[149] Ax WKoch LDevelopment of daunorubicin resistance in tumour cells by induction of carbonyl reduction..Biochem Pharmacol2000;59:293-300

[150] Gonzalez BDoroshow JKaplan WDProtection against Daunorubicin Cytotoxicity by Expression of a Cloned Human Carbonyl Reductase cDNA in K562 Leukemia Cells..Cancer Res1995;55:4646-50

[151] Ikeda RLau ESachidanandam KIsolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells..Int J Oncol2011;38:513-9

[152] Matsunaga TIida KBanno YInvolvement of the aldo-keto reductase, AKR1B10, in mitomycin-c resistance through reactive oxygen species-dependent mechanisms..Anticancer Drugs2011;22:402-8

[153] Hayes JDJowsey IRGlutathione transferases..Annu Rev Pharmacol Toxicol2005;45:51-88

[154] Noda EInoue TNagahara HPredictive value of expression of ERCC 1 and GST-p for 5-fluorouracil/oxaliplatin chemotherapy in advanced colorectal cancer..Hepatogastroenterology2012;59:130-3

[155] Romero-Lorca AGaibar MFernandez-Santander AImpacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients..PLoS One2015;10:e0132269PMC4503404

[156] Scotlandi KCastellani GNardi FOvercoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome..J Clin Oncol2009;27:2209-16

[157] Bachas SGunio DStructural contributions to multidrug recognition in the multidrug resistance (MDR) gene regulator, BmrR..Proc Natl Acad Sci U S A2011;108:11046-51PMC3131311

[158] Singh AZhang PMa JExpression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype..Mol Cancer Ther2010;9:2365-76PMC2955865

[159] Stockel BNies ATBrom MCharacterization of the 5’-flanking region of the human multidrug resistance protein 2 (MRP2) gene and its regulation in comparison withthe multidrug resistance protein 3 (MRP3) gene..Eur J Biochem2000;267:1347-58

[160] Xu SCai SYBoyer JLAryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression..Am J Physiol Gastrointest Liver Physiol2010;299:G126-35PMC2904108

[161] Shim GSShin DHKwak MKAcquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway..Free Radical Bio Med2009;47:1619-31

[162] Young LCCole SPCGerlach JHMultidrug Resistance Proteins MRP3, MRP1, and MRP2 in Lung Cancer..Clin Cancer Res2001;7:1798-804

[163] Halon ADonizy PRabczynski JMRP2 (ABCC2, cMOAT) expression in nuclear envelope of primary fallopian tube cancer cells is a new unfavorable prognostic factor..Arch Gynecol Obstet2013;287:563-70PMC3569580

[164] Materna VThomale JProtection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells..Int J Cancer2005;115:393-402

[165] Choi HKRoh SHKang KWInduction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells..Endocr Relat Cancer2007;14:293-303

[166] Zhang YHXiao XYWang XPSilencing MRP4 by small interfering RNA reverses acquired DDP resistance of gastric cancer cell..Cancer Lett2010;291:76-82

[167] Zhang LFan YF[Detection of multidrug resistance-associated proteins MRP2, MRP3, and MRP5 mRNA expressions in hepatocarcinoma cells using SYBR real-time PCR]..Nan Fang Yi Ke Da Xue Xue Bao2008;28:219-21

[168] Gao AMWang JNChen SYApigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway..Carcinogenesis2013;34:1806-14

[169] Nakanishi TDrug transporters as targets for cancer chemotherapy..Cancer Genom Proteom2007;4:241-54

[170] Huang YMembrane transporters and channels in chemoresistance and -sensitivity of tumor cells..Cancer Lett2006;239:168-82

[171] Esteras NAbramov Andrey YNrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function..In. Biological Chemistry;2016;383(ISBN No. 14316730)

[172] Januchowski RAndrzejewska MZabel MMicroarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines..Biomed Pharmacother2013;67:240-5

[173] Okuno SKuriyama-Matsumura KWang HRole of cystine transport in intracellular glutathione level and cisplatin resistance in human ovarian cancer cell lines..Br J Cancer2003;88:951-6PMC2377069

[174] Yin YWang BXu LExpression and function of heme oxygenase-1 in human gastric cancer..Exp Biol Med (Maywood)2012;237:362-71

[175] Jeon WKSeo WCLee HYSmad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition..Biochem Biophys Res Commun2012;420:288-92

[176] Heasman SABowles KMMacewan DJProtection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1..Oncotarget2011;2:658-68PMC3248221

[177] Nagai TOhmine KNakamura MHemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2..J Cell Biochem2008;104:680-91

[178] Basta PVTse CKSullivan PFGenetic variation in Transaldolase 1 and risk of squamous cell carcinoma of the head and neck..Cancer Detect Prev2008;32:200-8PMC2614275

[179] Cui YLiu CSchwartz CTUpregulation of glucose metabolism by NF-kappaB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells..Endocr Relat Cancer2014;21:435-42PMC4021715

[180] Wang ZLian XZhao SIdentification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis..Sci Rep2015;5:9301PMC4377623

[181] Zhang MBrumbaugh JRabii ROral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes..BMC Cancer2014;14:223PMC3972515

[182] Chen ZTang NLi ZThe histone acetylranseferase hMOF acetylates Nrf2 and regulates anti-drug responses in human non-small cell lung cancer..Br J Pharmacol2014;171:3196-211PMC4080974

[183] Shah NMMurray MYMacEwan DJUnderstanding the role of NRF2-regulated miRNAs in human malignancies..Oncotarget2013;4:1130-42PMC3787145

[184] Ceppi PKumarswamy RScagliotti GVLoss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer..Mol Cancer Res2010;8:1207-16

[185] Cochrane DRSpoelstra NSLoss of miR-200c: A Marker of Aggressiveness and Chemoresistance in Female Reproductive Cancers..J Oncol2010;2010:821717PMC2798671

[186] Liu SCui RmiR-200c inhibits melanoma progression and drug resistance through down-regulation of BMI-1..Am J Pathol2012;181:1823-35PMC3483804

[187] Lister AKitteringham NRCostello ENrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy..Mol cancer2011;10:37PMC3098205

[188] Khalil HSLangdon SPBown JQuantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells..J Biotechnol2015;202:12-30

[189] Kweon MHLee JSConstitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate..J Biol Chem2006;281:33761-72

[190] Jiang THigh levels of Nrf2 determine chemoresistance in type II endometrial cancer..Cancer Res2010;70:5486-96PMC2896449

[191] Stacy DRMassion PPHallahan DEIncreased expression of nuclear factor E2 p45□related factor 2 (NRF2) in head and neck squamous cell carcinomas..Head Neck2006;28:813-8

[192] Kim YSLee KBChung WYNuclear factor E2-related factor 2 dependent overexpression of sulfiredoxin and peroxiredoxin III in human lung cancer..Korean J Intern Med2011;26:304-13PMC3192203

[193] Ohta TMiyamoto MTanaka HLoss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth..Cancer Res2008;68:1303-9

[194] Shibata TTong KIOdogawa RCancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy..Proc Natl Acad Sci U S A2008;105:13568-73PMC2533230

[195] Pandey PSingh MShukla HSThe see-saw of Keap1-Nrf2 pathway in Cancer..Crit Rev Oncol Hematol2017;116:89-98

[196] No JHSong YSTargeting Nrf2 Signaling to Combat Chemoresistance..J Cancer2014;19:111-7PMC4204167

[197] Petroski MDFunction and regulation of cullin-RING ubiquitin ligases..Nat Rev Mol Cell Biol2005;6:9-20

[198] Skaar JRPagano MMechanisms and function of substrate recruitment by F-box proteins..Nat Rev Mol Cell Biol2013;14:369-81PMC3827686

[199] Chen HYCullin 3 Ubiquitin Ligases in Cancer Biology: Functions and Therapeutic Implications..Front Oncol2016;6:113PMC4852199

[200] Skaar JRPagano MSCF ubiquitin ligase-targeted therapies..Nat Rev Drug Discov2014;13:889-903PMC4410837

[201] Huang CChen CSmall interfering RNA therapy in cancer: mechanism, potential targets, and clinical applications..Expert Opin Ther Tar2008;12:637-45

[202] Guo WYu WDeng WSmall interfering RNA-based molecular therapy of cancers..Chin J Cancer2013;32:488PMC3845562

[203] Kanninen KMLeinonen HKoistinaho JApplications of the Keap1-Nrf2 system for gene and cell therapy..Free Radical Bio Med2015;88:350-61

[204] Duong HQOh SSeong YSSilencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells..Antioxidants2017;6:52PMC5618080

[205] Esmaeili MACombination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells..J Chem Bio2016;9:41-52PMC4733072

[206] Curtin NJDNA repair dysregulation from cancer driver to therapeutic target..Nat Rev Cancer2012;12:801-17

[207] Gorrini CHarris ISInoue SBRCA1 interacts with Nrf2 to regulate antioxidant signaling and cell survival..J Exp Med2013;210:1529-44PMC3727320

[208] Kang HJKim HJNath RGDetoxification: a novel function of BRCA1 in tumor suppression?.Toxicol Sci2011;122:26-37PMC3143468

[209] Gorrini CBassi CBaniasadi SPEstrogen controls the survival of BRCA1-deficient cells via a PI3K-NRF2-regulated pathway..Proc Natl Acad Sci U S A2014;111:4472-7PMC3970526

[210] Lee EYTissue-specific tumor suppression by BRCA1..Proc Natl Acad Sci U S A2014;111:4353-4PMC3970521

[211] Wu TTian WLau APoly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription..Free Radic Biol Med2014;67:69-80PMC3945083

[212] Khalil HSNRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response..BioDiscovery2015;15:1

[213] Wang QYang XGao SNrf2 is associated with the regulation of basal transcription activity of the BRCA1 gene..Acta Biochim Biophys Sin (Shanghai)2013;45:179-87

[214] Jayakumar SSandur SKNrf2 facilitates repair of radiation induced DNA damage through homologous recombination repair pathway in a ROS independent manner in cancer cells..Mutat Res2015;779:33-45

[215] Rojo de la Vega MChapman ENRF2-targeted therapeutics: New targets and modes of NRF2 regulation..Curr Opin Toxicol2016;1:62-70PMC5654570

[216] Bhullar KSMcGowan EMJha AKinase-targeted cancer therapies: progress, challenges and future directions..Mol Cancer2018;17:48PMC5817855

[217] Fabbro DBuchdunger EFendrich GProtein kinases as targets for anticancer agents: from inhibitors to useful drugs..Pharmacol Ther2002;93:79-98

[218] Mirshafiey AAsghari BReceptor Tyrosine Kinase and Tyrosine Kinase Inhibitors: New Hope for Success in Multiple Sclerosis Therapy..Innov Clin Neurosci2014;11:23-36PMC4204472

[219] Voldborg BRSpang-Thomsen MEpidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials..Ann Oncol1997;8:1197-206

[220] Yarden YUntangling the ErbB signalling network..Nat Rev Mol Cell Biol2001;2:127-37

[221] Tzahar EThe ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands..Biochim Biophys Acta1998;1377:M25-37

[222] Hackel POPrenzel NEpidermal growth factor receptors: critical mediators of multiple receptor pathways..Curr Opin Cell Biol1999;11:184-9

[223] Bange JUllrich AMolecular targets for breast cancer therapy and prevention..Nat Med2001;7:548-52

[224] Khalil HSKankia IHDeeni YYNRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted Immunotherapies..Oxid Med Cell Longev2016;2016:4148791PMC4685121

[225] Warfel NASong JHPIM Kinase Inhibitors Kill Hypoxic Tumor Cells by Reducing Nrf2 Signaling and Increasing Reactive Oxygen Species..Mol Cancer Ther2016;15:1637-47PMC4936950

[226] Duong HQKang HJTang WInhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine..Int J Oncol2014;44:959-69PMC3928470

[227] Yu RMandlekar SDer CJRole of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals..J Biol Chem1999;274:27545-52

[228] Yeh CTInvolvement of p38 MAPK and Nrf2 in phenolic acid-induced P-form phenol sulfotransferase expression in human hepatoma HepG2 cells..Carcinogenesis2006;27:1008-17

[229] Kang KAPark JWNa HKTriphlorethol-A induces heme oxygenase-1 via activation of ERK and NF-E2 related factor 2 transcription factor..FEBS Lett2007;581:2000-8

[230] Zhang HIles KEPostlethwait EM4-Hydroxynonenal induces rat gamma-glutamyl transpeptidase through mitogen-activated protein kinase-mediated electrophile response element/nuclear factor erythroid 2-related factor 2 signaling..Am J Respir Cell Mol Biol2006;34:174-81PMC2696200

[231] Huang HFu WZhou LDownregulation of Keap1 contributes to poor prognosis and Axitinib resistance of renal cell carcinoma via upregulation of Nrf2 expression..Int J Mol Med2019;43:2044-54PMC6443340

[232] Ji SZhao XYu LQEffect of the Nrf2-ARE signaling pathway on biological characteristics and sensitivity to sunitinib in renal cell carcinoma..Oncol Lett2019;17:5175-86PMC6507454

[233] Ma SYan TMajor MBTargeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target..Ann N Y Acad Sci2018;1434:164-72PMC6230513

[234] Tsuchida KHayashi MKeleku-Lukwete NHalofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation..Free Radic Biol Med2017;103:236-47

[235] Choi EJLee SHShin EAA clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer..Oncogene2017;36:5285

[236] Wu TWong PKZhang DDOxidative stress, mammospheres and Nrf2-new implication for breast cancer therapy?.Mol Carcinog2015;54:1494-502PMC4697962

[237] Wang HGeng MWu XRXRα Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2..Cancer Res2013;73:3097-108

[238] Kang KAOxidative Stress, Nrf2, and Epigenetic Modification Contribute to Anticancer Drug Resistance..Toxicol Res2017;33:1-5PMC5266370

[239] Zhang HChen HYHistone deacetylases function as novel potential therapeutic targets for cancer..Hepatol Res2017;47:149-59

[240] Yu JJZhao FJmiR-96 promotes cell proliferation and clonogenicity by down-regulating of FOXO1 in prostate cancer cells..Med Oncol2014;31:910

[241] Yi TZHan XQu QDNMT inhibitors and HDAC inhibitors regulate E-cadherin and Bcl-2 expression in endometrial carcinoma in vitro and in vivo..Chemotherapy2012;58:19-29

[242] Verma MCancer control and prevention: nutrition and epigenetics..Curr Opin Clin Nutr Metab Care2013;16:376-84

[243] Reichert NMatthias PMultiple roles of class I HDACs in proliferation, differentiation, and development..Cell Mol Life Sci2012;69:2173-87

[244] Zhang CKhor TOKong ANSulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation..Biochem Pharmacol2013;85:1398-404PMC4123317

[245] Su ZYLee JHWu TYRequirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA-induced mouse skin cell transformation by sulforaphane..Cancer Prev Res (Phila)2014;7:319-29

[246] Hu CMesecar ADModification of keap1 cysteine residues by sulforaphane..Chem Res Toxicol2011;24:515-21PMC3086360

[247] Kensler TWAgyeman ASGroopman JDKeap1-nrf2 signaling: a target for cancer prevention by sulforaphane..Top Curr Chem2013;329:163-77PMC3553557

[248] Kang KAKim KCChang WYEpigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation..Cell Death Dis2014;5:e1183PMC4001304

[249] Shilatifard AMolecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation..Curr Opin Cell Biol2008;20:341-8PMC2504688

[250] Khor TOWu TYLee JPharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation..Biochem Pharmacol2011;82:1073-8

[251] Paredes-Gonzalez XSu ZYApigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications..AAPS J2014;16:727-35PMC4070251

[252] Wang LGuo YYang YBlocking of JB6 cell transformation by tanshinone IIA: epigenetic reactivation of Nrf2 antioxidative stress pathway..AAPS J2014;16:1214-25PMC4389756

[253] Wu TYSu ZYShu LEpigenetic modifications of Nrf2 by 3,3’-diindolylmethane in vitro in TRAMP C1 cell line and in vivo TRAMP prostate tumors..AAPS J2013;15:864-74PMC3691436

[254] Lee OHPapusha VAn auto-regulatory loop between stress sensors INrf2 and Nrf2 controls their cellular abundance..J Biol Chem2007;282:36412-20

[255] Xu CPan ZKim JHMechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2..Mol Cancer Ther2006;5:1918-26

[256] Owuor EDAntioxidants and oxidants regulated signal transduction pathways..Biochem Pharmacol2002;64:765-70

[257] Jain ASjøttem EAtesoh Awuh Jp62/SQSTM1 Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription..J Biol Chem2010;285:22576-91PMC2903417

[258] Papp DMódos DDúl ZThe NRF2-related interactome and regulome contain multifunctional proteins and fine-tuned autoregulatory loops..FEBS Lett2012;586:1795-802

[259] Khalil HSLangdon SPBown JQuantitative analysis of NRF2 pathway reveals key elements of the regulatory circuits underlying antioxidant response and proliferation of ovarian cancer cells..J Biotechnol2015;202:12-30