1932

Abstract

The unregulated proliferative capacity of many tumors is dependent on dysfunctional nutrient utilization and ROS (reactive oxygen species) signaling to sustain a deranged metabolic state. Although it is clear that cancers broadly rely on these survival and signaling pathways, how they achieve these aims varies dramatically. Mutations in the KEAP1/NRF2 pathway represent a potent cancer adaptation to exploit native cytoprotective pathways that involve both nutrient metabolism and ROS regulation. Despite activating these advantageous processes, mutations within / are not universally selected for across cancers and instead appear to interact with particular tumor driver mutations and tissues of origin. Here, we highlight the relationship between the KEAP1/NRF2 signaling axis and tumor biology with a focus on genetic mutation, metabolism, immune regulation, and treatment implications and opportunities. Understanding the dysregulation of KEAP1 and NRF2 provides not only insight into a commonly mutated tumor suppressor pathway but also a window into the factors dictating the development and evolution of many cancers.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030518-055627
2020-03-04
2024-06-17
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/4/1/annurev-cancerbio-030518-055627.html?itemId=/content/journals/10.1146/annurev-cancerbio-030518-055627&mimeType=html&fmt=ahah

Literature Cited

  1. Adam J, Hatipoglu E, O'Flaherty L, Ternette N, Sahgal N et al. 2011. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20:524–37
    [Google Scholar]
  2. Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P 2002. The evolution of electron-transport chains. Molecular Biology of the Cell821–29 New York: Garland Sci. , 4th ed..
    [Google Scholar]
  3. Alpha-Tocopherol Beta Carotene Cancer Prev. Study Group 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330:1029–35
    [Google Scholar]
  4. Arbour KC, Jordan E, Kim HR, Dienstag J, Yu HA et al. 2018. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24:334–40
    [Google Scholar]
  5. Baird L, Swift S, Lleres D, Dinkova-Kostova AT 2014. Monitoring Keap1-Nrf2 interactions in single live cells. Biotechnol. Adv. 32:1133–44
    [Google Scholar]
  6. Bar-Peled L, Kemper EK, Suciu RM, Vinogradova EV, Backus KM et al. 2017. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171:696–709.e23
    [Google Scholar]
  7. Bauer AK, Cho HY, Miller-Degraff L, Walker C, Helms K et al. 2011. Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice. PLOS ONE 6:e26590
    [Google Scholar]
  8. Berger AH, Brooks AN, Wu X, Shrestha Y, Chouinard C et al. 2016. High-throughput phenotyping of lung cancer somatic mutations. Cancer Cell 30:214–28
    [Google Scholar]
  9. Best SA, De Souza DP, Kersbergen A, Policheni AN, Dayalan S et al. 2018. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab 27:935–43.e4
    [Google Scholar]
  10. Bhatt V, Khayati K, Hu ZS, Lee A, Kamran W et al. 2019. Autophagy modulates lipid metabolism to maintain metabolic flexibility for Lkb1-deficient Kras-driven lung tumorigenesis. Genes Dev 33:150–65
    [Google Scholar]
  11. Blake DJ, Singh A, Kombairaju P, Malhotra D, Mariani TJ et al. 2010. Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation. Am. J. Respir. Cell Mol. Biol. 42:524–36
    [Google Scholar]
  12. Bollong MJ, Lee G, Coukos JS, Yun H, Zambaldo C et al. 2018. A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling. Nature 562:600–4
    [Google Scholar]
  13. Bomont P, Cavalier L, Blondeau F, Ben Hamida C, Belal S et al. 2000. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat. Genet. 26:370–74
    [Google Scholar]
  14. Brogden KA, Parashar D, Hallier AR, Braun T, Qian F et al. 2018. Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy. BMC Cancer 18:225
    [Google Scholar]
  15. Cancer Genome Atlas Res. Netw 2012. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489:519–25
    [Google Scholar]
  16. Cancer Genome Atlas Res. Netw 2014. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543–50
    [Google Scholar]
  17. Cancer Genome Atlas Res. Netw 2017. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169:1327–41.e23
    [Google Scholar]
  18. Cancer Genome Atlas Res. Netw., Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ et al. 2016. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374:135–45
    [Google Scholar]
  19. Cao JY, Poddar A, Magtanong L, Lumb JH, Mileur TR et al. 2019. A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep 26:1544–56.e8
    [Google Scholar]
  20. Cardnell RJ, Behrens C, Diao L, Fan Y, Tang X et al. 2015. An integrated molecular analysis of lung adenocarcinomas identifies potential therapeutic targets among TTF1-negative tumors, including DNA repair proteins and Nrf2. Clin. Cancer Res. 21:3480–91
    [Google Scholar]
  21. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T et al. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–41
    [Google Scholar]
  22. Chen F, Zhang Y, Senbabaoglu Y, Ciriello G, Yang L et al. 2016. Multilevel genomics-based taxonomy of renal cell carcinoma. Cell Rep 14:2476–89
    [Google Scholar]
  23. Chen PH, Smith TJ, Wu J, Siesser PF, Bisnett BJ et al. 2017. Glycosylation of KEAP1 links nutrient sensing to redox stress signaling. EMBO J 36:2233–50
    [Google Scholar]
  24. Chian S, Thapa R, Chi Z, Wang XJ, Tang X 2014. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo. Biochem. Biophys. Res. Commun. 447:602–8
    [Google Scholar]
  25. Chio C II, Jafarnejad SM, Ponz-Sarvise M, Park Y, Rivera K et al. 2016. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166:963–76
    [Google Scholar]
  26. Choi EJ, Jung BJ, Lee SH, Yoo HS, Shin EA et al. 2017. A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer. Oncogene 36:5285–95
    [Google Scholar]
  27. Copple IM, Lister A, Obeng AD, Kitteringham NR, Jenkins RE et al. 2010. Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway. J. Biol. Chem. 285:16782–88
    [Google Scholar]
  28. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E et al. 2018. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362:eaar3593
    [Google Scholar]
  29. Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP et al. 2019. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18:4295–317
    [Google Scholar]
  30. Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A et al. 2015. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161:1527–38
    [Google Scholar]
  31. DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z et al. 2015. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47:1475–81
    [Google Scholar]
  32. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C et al. 2011. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–9
    [Google Scholar]
  33. Ebihara S, Tajima H, Ono M 2016. Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis. Arthritis Res. Ther. 18:139
    [Google Scholar]
  34. Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M et al. 2006. p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J. Biol. Chem. 281:39776–84
    [Google Scholar]
  35. Frank R, Scheffler M, Merkelbach-Bruse S, Ihle MA, Kron A et al. 2018. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin. Cancer Res. 24:3087–96
    [Google Scholar]
  36. Frezza C, Zheng L, Folger O, Rajagopalan KN, MacKenzie ED et al. 2011. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477:225–28
    [Google Scholar]
  37. Gacesa R, Dunlap WC, Barlow DJ, Laskowski RA, Long PF 2016. Rising levels of atmospheric oxygen and evolution of Nrf2. Sci. Rep. 6:27740
    [Google Scholar]
  38. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L et al. 2012. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat. Genet. 44:694–98
    [Google Scholar]
  39. Gwinn DM, Lee AG, Briones-Martin-Del-Campo M, Conn CS, Simpson DR et al. 2018. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33:91–107.e6
    [Google Scholar]
  40. Hamada S, Shimosegawa T, Taguchi K, Nabeshima T, Yamamoto M, Masamune A 2018. Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma. Am. J. Physiol. Gastrointest. Liver Physiol. 314:G65–74
    [Google Scholar]
  41. Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100:57–70
    [Google Scholar]
  42. Hao JJ, Lin DC, Dinh HQ, Mayakonda A, Jiang YY et al. 2016. Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma. Nat. Genet. 48:1500–7
    [Google Scholar]
  43. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C et al. 2015. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27:211–22
    [Google Scholar]
  44. Hast BE, Cloer EW, Goldfarb D, Li H, Siesser PF et al. 2014. Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. Cancer Res 74:808–17
    [Google Scholar]
  45. Hast BE, Goldfarb D, Mulvaney KM, Hast MA, Siesser PF et al. 2013. Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Cancer Res 73:2199–210
    [Google Scholar]
  46. Hayes JD, Dinkova-Kostova AT. 2017. Oncogene-stimulated congestion at the KEAP1 stress signaling hub allows bypass of NRF2 and induction of NRF2-target genes that promote tumor survival. Cancer Cell 32:539–41
    [Google Scholar]
  47. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB et al. 2005. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–83
    [Google Scholar]
  48. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X et al. 2015. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–28
    [Google Scholar]
  49. Holland HD. 2006. The oxygenation of the atmosphere and oceans. Philos. Trans. R. Soc. Lond. B 361:903–15
    [Google Scholar]
  50. Hubbs AF, Benkovic SA, Miller DB, O'Callaghan JP, Battelli L et al. 2007. Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2. Am. J. Pathol. 170:2068–76
    [Google Scholar]
  51. Huppke P, Weissbach S, Church JA, Schnur R, Krusen M et al. 2017. Activating de novo mutations in NFE2L2 encoding NRF2 cause a multisystem disorder. Nat. Commun. 8:818
    [Google Scholar]
  52. Igarashi K, Kataoka K, Itoh K, Hayashi N, Nishizawa M, Yamamoto M 1994. Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins. Nature 367:568–72
    [Google Scholar]
  53. Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ et al. 1997. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275:1649–52
    [Google Scholar]
  54. Ito A, Shimazu T, Maeda S, Shah AA, Tsunoda T et al. 2015. The subcellular localization and activity of cortactin is regulated by acetylation and interaction with Keap1. Sci. Signal. 8:ra120
    [Google Scholar]
  55. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K et al. 1997. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236:313–22
    [Google Scholar]
  56. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K et al. 1999. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86
    [Google Scholar]
  57. Jain A, Lamark T, Sjottem E, Larsen KB, Awuh JA et al. 2010. p62/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. Chem. 285:22576–91
    [Google Scholar]
  58. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK et al. 2017. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376:2109–21
    [Google Scholar]
  59. Jang J, Wang Y, Kim HS, Lalli MA, Kosik KS 2014. Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells. Stem Cells 32:2616–25
    [Google Scholar]
  60. Jordan EJ, Kim HR, Arcila ME, Barron D, Chakravarty D et al. 2017. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov 7:596–609
    [Google Scholar]
  61. Kadara H, Choi M, Zhang J, Parra ER, Rodriguez-Canales J et al. 2017. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Ann. Oncol. 28:75–82
    [Google Scholar]
  62. Kadara H, Sivakumar S, Jakubek Y, San Lucas FA, Lang W et al. 2019. Driver mutations in normal airway epithelium elucidate spatiotemporal resolution of lung cancer. Am. J. Respir. Crit. Care Med. 200:742–50
    [Google Scholar]
  63. Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M 2004. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. PNAS 101:2046–51
    [Google Scholar]
  64. Kang YP, Torrente L, Falzone A, Elkins CM, Liu M et al. 2019. Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer. eLife 8:e45572
    [Google Scholar]
  65. Kaufman JM, Amann JM, Park K, Arasada RR, Li H et al. 2014. LKB1 loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT. J. Thorac. Oncol. 9:794–804
    [Google Scholar]
  66. Kerins MJ, Ooi A. 2018. A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci. Rep. 8:12846
    [Google Scholar]
  67. Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE et al. 2013. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155:552–66
    [Google Scholar]
  68. Kim YR, Oh JE, Kim MS, Kang MR, Park SW et al. 2010. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J. Pathol. 220:446–51
    [Google Scholar]
  69. Kinch L, Grishin NV, Brugarolas J 2011. Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type 2. Cancer Cell 20:418–20
    [Google Scholar]
  70. Kitamura H, Onodera Y, Murakami S, Suzuki T, Motohashi H 2017. IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model. Oncogene 36:6315–24
    [Google Scholar]
  71. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS et al. 2011. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306:1549–56
    [Google Scholar]
  72. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y et al. 2004. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 24:7130–39
    [Google Scholar]
  73. Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M et al. 2016. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7:11624
    [Google Scholar]
  74. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A et al. 2010. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12:213–23
    [Google Scholar]
  75. Konstantinopoulos PA, Spentzos D, Fountzilas E, Francoeur N, Sanisetty S et al. 2011. Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res 71:5081–89
    [Google Scholar]
  76. Koppula P, Zhang Y, Shi J, Li W, Gan B 2017. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. J. Biol. Chem. 292:14240–49
    [Google Scholar]
  77. Korytina GF, Akhmadishina LZ, Aznabaeva YG, Kochetova OV, Zagidullin NS et al. 2019. Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease. Gene 692:102–12
    [Google Scholar]
  78. Krall EB, Wang B, Munoz DM, Ilic N, Raghavan S et al. 2017. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. eLife 6:e18970
    [Google Scholar]
  79. Lahiri P, Schmidt V, Smole C, Kufferath I, Denk H et al. 2016. p62/sequestosome-1 is indispensable for maturation and stabilization of Mallory-Denk bodies. PLOS ONE 11:e0161083
    [Google Scholar]
  80. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T et al. 2010. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol. Cell Biol. 30:3275–85
    [Google Scholar]
  81. Lee AC, Fenster BE, Ito H, Takeda K, Bae NS et al. 1999. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274:7936–40
    [Google Scholar]
  82. Lee DF, Kuo HP, Liu M, Chou CK, Xia W et al. 2009. KEAP1 E3 ligase-mediated downregulation of NF-κB signaling by targeting IKKβ. Mol. Cell 36:131–40
    [Google Scholar]
  83. Li L, Shen C, Nakamura E, Ando K, Signoretti S et al. 2013. SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer. Cancer Cell 24:738–50
    [Google Scholar]
  84. Li QK, Singh A, Biswal S, Askin F, Gabrielson E 2011. KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma. J. Hum. Genet. 56:230–34
    [Google Scholar]
  85. Lignitto L, LeBoeuf SE, Homer H, Jiang S, Askenazi M et al. 2019. Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1. Cell 178:316–29.e18
    [Google Scholar]
  86. Ling J, Kang Y, Zhao R, Xia Q, Lee DF et al. 2012. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 21:105–20
    [Google Scholar]
  87. Liu X, Cooper DE, Cluntun AA, Warmoes MO, Zhao S et al. 2018. Acetate production from glucose and coupling to mitochondrial metabolism in mammals. Cell 175:502–13.e13
    [Google Scholar]
  88. Lo SC, Hannink M. 2008. PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria. Exp. Cell Res. 314:1789–803
    [Google Scholar]
  89. Ludtmann MH, Angelova PR, Zhang Y, Abramov AY, Dinkova-Kostova AT 2014. Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem. J. 457:415–24
    [Google Scholar]
  90. Ma J, Cai H, Wu T, Sobhian B, Huo Y et al. 2012. PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function. Mol. Cell. Biol. 32:1506–17
    [Google Scholar]
  91. Ma Q, Battelli L, Hubbs AF 2006. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am. J. Pathol. 168:1960–74
    [Google Scholar]
  92. Maj T, Wang W, Crespo J, Zhang H, Wang W et al. 2017. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18:1332–41
    [Google Scholar]
  93. Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F et al. 2018. Somatic mutant clones colonize the human esophagus with age. Science 362:911–17
    [Google Scholar]
  94. Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM et al. 2016. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353:1161–65
    [Google Scholar]
  95. McDonald ER III, de Weck A, Schlabach MR, Billy E, Mavrakis KJ et al. 2017. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170:577–92.e10
    [Google Scholar]
  96. McMillan EA, Ryu MJ, Diep CH, Mendiratta S, Clemenceau JR et al. 2018. Chemistry-first approach for nomination of personalized treatment in lung cancer. Cell 173:864–78.e29
    [Google Scholar]
  97. Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D et al. 2018. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556:113–17
    [Google Scholar]
  98. Mitchell TJ, Turajlic S, Rowan A, Nicol D, Farmery JHR et al. 2018. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173:611–23.e17
    [Google Scholar]
  99. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T et al. 2012. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22:66–79
    [Google Scholar]
  100. Murakami S, Shimizu R, Romeo PH, Yamamoto M, Motohashi H 2014. Keap1-Nrf2 system regulates cell fate determination of hematopoietic stem cells. Genes Cells 19:239–53
    [Google Scholar]
  101. Nishina T, Deguchi Y, Miura R, Yamazaki S, Shinkai Y et al. 2017. Critical contribution of nuclear factor erythroid 2-related factor 2 (NRF2) to electrophile-induced interleukin-11 production. J. Biol. Chem. 292:205–16
    [Google Scholar]
  102. Okawa H, Motohashi H, Kobayashi A, Aburatani H, Kensler TW, Yamamoto M 2006. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339:79–88
    [Google Scholar]
  103. Olagnier D, Brandtoft AM, Gunderstofte C, Villadsen NL, Krapp C et al. 2018. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9:3506
    [Google Scholar]
  104. Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V et al. 2011. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20:511–23
    [Google Scholar]
  105. Orru C, Szydlowska M, Taguchi K, Zavattari P, Perra A et al. 2018. Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis. J. Hepatol. 69:635–43
    [Google Scholar]
  106. Pae HO, Oh GS, Lee BS, Rim JS, Kim YM, Chung HT 2006. 3-Hydroxyanthranilic acid, one of l-tryptophan metabolites, inhibits monocyte chemoattractant protein-1 secretion and vascular cell adhesion molecule-1 expression via heme oxygenase-1 induction in human umbilical vein endothelial cells. Atherosclerosis 187:274–84
    [Google Scholar]
  107. Pajares M, Jimenez-Moreno N, Garcia-Yague AJ, Escoll M, de Ceballos ML et al. 2016. Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12:1902–16
    [Google Scholar]
  108. Paul MK, Bisht B, Darmawan DO, Chiou R, Ha VL et al. 2014. Dynamic changes in intracellular ROS levels regulate airway basal stem cell homeostasis through Nrf2-dependent Notch signaling. Cell Stem Cell 15:199–214
    [Google Scholar]
  109. Pekovic-Vaughan V, Gibbs J, Yoshitane H, Yang N, Pathiranage D et al. 2014. The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. Genes Dev 28:548–60
    [Google Scholar]
  110. Pi J, Leung L, Xue P, Wang W, Hou Y et al. 2010. Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J. Biol. Chem. 285:9292–300
    [Google Scholar]
  111. Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, Cuadrado A 2011. SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol. Cell. Biol. 31:1121–33
    [Google Scholar]
  112. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A et al. 2011. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. PNAS 108:1433–38
    [Google Scholar]
  113. Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T et al. 2010. Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J. Cell Biol. 191:537–52
    [Google Scholar]
  114. Romero R, Sayin VI, Davidson SM, Bauer MR, Singh SX et al. 2017. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23:1362–68
    [Google Scholar]
  115. Saddawi-Konefka R, Seelige R, Gross ET, Levy E, Searles SC et al. 2016. Nrf2 induces IL-17D to mediate tumor and virus surveillance. Cell Rep 16:2348–58
    [Google Scholar]
  116. Saito T, Ichimura Y, Taguchi K, Suzuki T, Mizushima T et al. 2016. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat. Commun. 7:12030
    [Google Scholar]
  117. Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A 2006. Glycogen synthase kinase-3β inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J. Biol. Chem. 281:14841–51
    [Google Scholar]
  118. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A et al. 2018. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell 173:321–37.e10
    [Google Scholar]
  119. Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y et al. 2013. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat. Genet. 45:860–67
    [Google Scholar]
  120. Satoh H, Moriguchi T, Taguchi K, Takai J, Maher JM et al. 2010. Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis 31:1833–43
    [Google Scholar]
  121. Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M 2013. Nrf2 prevents initiation but accelerates progression through the Kras signaling pathway during lung carcinogenesis. Cancer Res 73:4158–68
    [Google Scholar]
  122. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO 2014. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med. 6:221ra15
    [Google Scholar]
  123. Sayin VI, LeBoeuf SE, Singh SX, Davidson SM, Biancur D et al. 2017. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. eLife 6:e28083
    [Google Scholar]
  124. Schafer M, Dutsch S, auf dem Keller U, Navid F, Schwarz A et al. 2010. Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis. Genes Dev 24:1045–58
    [Google Scholar]
  125. Schulte ML, Fu A, Zhao P, Li J, Geng L et al. 2018. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat. Med. 24:194–202
    [Google Scholar]
  126. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J et al. 2015. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47:505–11
    [Google Scholar]
  127. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L et al. 2003. Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci. 23:3394–406
    [Google Scholar]
  128. Singh A, Bodas M, Wakabayashi N, Bunz F, Biswal S 2010. Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid. Redox. Signal. 13:1627–37
    [Google Scholar]
  129. Singh A, Misra V, Thimmulappa RK, Lee H, Ames S et al. 2006. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLOS Med 3:e420
    [Google Scholar]
  130. Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC et al. 2010. Nrf2 and Keap1 abnormalities in non–small cell lung carcinoma and association with clinicopathologic features. Clin. Cancer Res. 16:3743–53
    [Google Scholar]
  131. Stafford WC, Peng X, Olofsson MH, Zhang X, Luci DK et al. 2018. Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy. Sci. Transl. Med. 10:eaaf7444
    [Google Scholar]
  132. Suzuki T, Maher J, Yamamoto M 2011. Select heterozygous Keap1 mutations have a dominant-negative effect on wild-type Keap1 in vivo. . Cancer Res 71:1700–9
    [Google Scholar]
  133. Suzuki T, Seki S, Hiramoto K, Naganuma E, Kobayashi EH et al. 2017. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus. Nat. Commun. 8:14577
    [Google Scholar]
  134. Suzuki T, Yamamoto M. 2015. Molecular basis of the Keap1-Nrf2 system. Free Radic. Biol. Med. 88:93–100
    [Google Scholar]
  135. Taguchi K, Fujikawa N, Komatsu M, Ishii T, Unno M et al. 2012. Keap1 degradation by autophagy for the maintenance of redox homeostasis. PNAS 109:13561–66
    [Google Scholar]
  136. Tamberg N, Tahk S, Koit S, Kristjuhan K, Kasvandik S et al. 2018. Keap1-MCM3 interaction is a potential coordinator of molecular machineries of antioxidant response and genomic DNA replication in metazoa. Sci. Rep. 8:12136
    [Google Scholar]
  137. Teshiba R, Tajiri T, Sumitomo K, Masumoto K, Taguchi T, Yamamoto K 2013. Identification of a KEAP1 germline mutation in a family with multinodular goitre. PLOS ONE 8:e65141
    [Google Scholar]
  138. Umemura A, He F, Taniguchi K, Nakagawa H, Yamachika S et al. 2016. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29:935–48
    [Google Scholar]
  139. Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H et al. 2013. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol. Cell. Biol. 33:2996–3010
    [Google Scholar]
  140. Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA 2008. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J. Neurosci. 28:13574–81
    [Google Scholar]
  141. Vargas MR, Pehar M, Cassina P, Beckman JS, Barbeito L 2006. Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J. Neurochem. 97:687–96
    [Google Scholar]
  142. Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S et al. 2003. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat. Genet. 35:238–45
    [Google Scholar]
  143. Wang Y, Han C, Lu L, Magliato S, Wu T 2013. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 58:995–1010
    [Google Scholar]
  144. Weerapana E, Wang C, Simon GM, Richter F, Khare S et al. 2010. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468:790–95
    [Google Scholar]
  145. Westcott PM, Halliwill KD, To MD, Rashid M, Rust AG et al. 2015. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517:489–92
    [Google Scholar]
  146. Xue F, Cooley L. 1993. kelch encodes a component of intercellular bridges in Drosophila egg chambers. Cell 72:681–93
    [Google Scholar]
  147. Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N et al. 2001. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60:1343–53
    [Google Scholar]
  148. Yoshida E, Suzuki T, Morita M, Taguchi K, Tsuchida K et al. 2018. Hyperactivation of Nrf2 leads to hypoplasia of bone in vivo. Genes Cells 23:386–92
    [Google Scholar]
  149. Yu HA, Suzawa K, Jordan E, Zehir A, Ni A et al. 2018. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24:3108–18
    [Google Scholar]
  150. Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M 2004. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol. Cell. Biol. 24:10941–53
    [Google Scholar]
  151. Zhou XL, Zhu CY, Wu ZG, Guo X, Zou W 2019. The oncoprotein HBXIP competitively binds KEAP1 to activate NRF2 and enhance breast cancer cell growth and metastasis. Oncogene 38:4028–46
    [Google Scholar]
  152. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK et al. 2019. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 10:1617
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030518-055627
Loading
/content/journals/10.1146/annurev-cancerbio-030518-055627
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error