Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers.
CCAAT-Enhancer-Binding Protein-beta
/ metabolism
Carcinogenesis
/ genetics
Carcinogens
Carcinoma, Non-Small-Cell Lung
/ genetics
Cell Line, Tumor
Enhancer Elements, Genetic
Epigenomics
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
/ genetics
NF-E2-Related Factor 2
/ metabolism
Signal Transduction
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 11 2020
20 11 2020
Historique:
received:
21
04
2020
accepted:
21
10
2020
entrez:
21
11
2020
pubmed:
22
11
2020
medline:
15
12
2020
Statut:
epublish
Résumé
Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.
Identifiants
pubmed: 33219226
doi: 10.1038/s41467-020-19593-0
pii: 10.1038/s41467-020-19593-0
pmc: PMC7679411
doi:
Substances chimiques
CCAAT-Enhancer-Binding Protein-beta
0
CEBPB protein, human
0
Carcinogens
0
NF-E2-Related Factor 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5911Commentaires et corrections
Type : ErratumIn
Références
Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional addiction in cancer. Cell 168, 629–643 (2017).
pubmed: 28187285
pmcid: 5308559
doi: 10.1016/j.cell.2016.12.013
Sengupta, S. & George, R. E. Super-enhancer-driven transcriptional dependencies in cancer. Trends Cancer 3, 269–281 (2017).
pubmed: 28718439
pmcid: 5546010
doi: 10.1016/j.trecan.2017.03.006
Chen, Y. et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat. Med. 19, 1023–1029 (2013).
pubmed: 23817021
pmcid: 3737318
doi: 10.1038/nm.3216
Denny, S. K. et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell 166, 328–342 (2016).
pubmed: 27374332
pmcid: 5004630
doi: 10.1016/j.cell.2016.05.052
Yamamoto, M., Kensler, T. W. & Motohashi, H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev. 98, 1169–1203 (2018).
pubmed: 29717933
doi: 10.1152/physrev.00023.2017
Singh, A. et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 3, e420 (2006).
pubmed: 17020408
pmcid: 1584412
doi: 10.1371/journal.pmed.0030420
Shibata, T. et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc. Natl Acad. Sci. USA 105, 13568–13573 (2008).
doi: 10.1073/pnas.0806268105
pubmed: 18757741
pmcid: 2533230
Inoue, D. et al. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma. Cancer Sci. 103, 760–766 (2012).
pubmed: 22320446
pmcid: 7659245
doi: 10.1111/j.1349-7006.2012.02216.x
Ooi, A. et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20, 511–523 (2011).
doi: 10.1016/j.ccr.2011.08.024
pubmed: 22014576
Adam, J. et al. 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, 524–537 (2011).
pubmed: 22014577
pmcid: 3202623
doi: 10.1016/j.ccr.2011.09.006
Onodera, Y. et al. NRF2 immunolocalization in human breast cancer patients as a prognostic factor. Endocr. Relat. Cancer 21, 241–252 (2014).
doi: 10.1530/ERC-13-0234
pubmed: 24302665
Kanamori, M. et al. Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients. Neuro Oncol. 17, 555–565 (2015).
doi: 10.1093/neuonc/nou282
pubmed: 25304134
Wang, X. J. et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29, 1235–1243 (2008).
pubmed: 18413364
pmcid: 3312612
doi: 10.1093/carcin/bgn095
Singh, A., Bodas, M., Wakabayashi, N., Bunz, F. & Biswal, S. Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid. Redox Signal. 13, 1627–1637 (2010).
pubmed: 20446773
pmcid: 3541552
doi: 10.1089/ars.2010.3219
Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).
pubmed: 22789539
doi: 10.1016/j.ccr.2012.05.016
DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet 47, 1475–1481 (2015).
pubmed: 26482881
pmcid: 4721512
doi: 10.1038/ng.3421
Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med 23, 1362–1368 (2017).
pubmed: 28967920
pmcid: 5677540
doi: 10.1038/nm.4407
Chio, I. I. et al. NRF2 promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166, 963–976 (2016).
pubmed: 27477511
pmcid: 5234705
doi: 10.1016/j.cell.2016.06.056
Kitamura, H., Onodera, Y., Murakami, S., Suzuki, T. & Motohashi, H. IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model. Oncogene 36, 6315–6324 (2017).
doi: 10.1038/onc.2017.236
pubmed: 28714957
Maher, J. M. et al. Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46, 1597–1610 (2007).
pubmed: 17668877
doi: 10.1002/hep.21831
Hong, Y. B. et al. Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells. Pancreas 39, 463–472 (2010).
pubmed: 20118824
pmcid: 3506252
doi: 10.1097/MPA.0b013e3181c31314
Kitamura, H. & Motohashi, H. NRF2 addiction in cancer cells. Cancer Sci. 109, 900–911 (2018).
pubmed: 29450944
pmcid: 5891176
doi: 10.1111/cas.13537
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer. Cell Subpopul. Cell 141, 69–80 (2010).
pubmed: 20371346
Eyler, C. E. & Rich, J. N. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J. Clin. Oncol. 26, 2839–2845 (2008).
pubmed: 18539962
doi: 10.1200/JCO.2007.15.1829
Jia, Y., Chen, J., Zhu, H., Jia, Z. H. & Cui, M. H. Aberrantly elevated redox sensing factor Nrf2 promotes cancer stem cell survival via enhanced transcriptional regulation of ABCG2 and Bcl-2/Bmi-1 genes. Oncol. Rep. 34, 2296–2304 (2015).
pubmed: 26324021
doi: 10.3892/or.2015.4214
Ryoo, I. G., Choi, B. H., Ku, S. K. & Kwak, M. K. High CD44 expression mediates p62-associated NFE2L2/NRF2 activation in breast cancer stem cell-like cells: Implications for cancer stem cell resistance. Redox Biol. 17, 246–258 (2018).
pubmed: 29729523
pmcid: 6006726
doi: 10.1016/j.redox.2018.04.015
Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).
pubmed: 24132290
pmcid: 3927368
doi: 10.1038/nature12634
Network, C.G.A.R. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 489, 519–525 (2012).
Network, C.G.A.R. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 511, 543–550 (2014).
Saigusa, D. et al. Impacts of NRF2 activation in non-small-cell lung cancer cell lines on extracellular metabolites. Cancer Sci. 111, 667–678 (2020).
pubmed: 31828882
pmcid: 7004536
doi: 10.1111/cas.14278
Justilien, V. et al. The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell 25, 139–151 (2014).
pubmed: 24525231
pmcid: 3949484
doi: 10.1016/j.ccr.2014.01.008
Zheng, Y. et al. A rare population of CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal. Cancer Cell 24, 59–74 (2013).
pubmed: 23845442
pmcid: 3923526
doi: 10.1016/j.ccr.2013.05.021
Ye, Y. Z. et al. Notch3 overexpression associates with poor prognosis in human non-small-cell lung cancer. Med. Oncol. 30, 595 (2013).
pubmed: 23645556
doi: 10.1007/s12032-013-0595-7
Katoh, Y. et al. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6, 857–868 (2001).
pubmed: 11683914
doi: 10.1046/j.1365-2443.2001.00469.x
Zhang, J. et al. Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes. Biochem. J. 404, 459–466 (2007).
pubmed: 17313370
pmcid: 1896277
doi: 10.1042/BJ20061611
Sekine, H. et al. The mediator subunit MED16 transduces NRF2-activating signals into antioxidant gene expression. Mol. Cell Biol. 36, 407–420 (2015).
pubmed: 26572828
doi: 10.1128/MCB.00785-15
Wakabayashi, N. et al. Notch-Nrf2 axis: regulation of Nrf2 gene expression and cytoprotection by notch signaling. Mol. Cell Biol. 34, 653–663 (2014).
pubmed: 24298019
pmcid: 3911489
doi: 10.1128/MCB.01408-13
Bar-Peled, L. et al. Chemical proteomics identifies druggable vulnerabilities in a genetically defined cancer. Cell 171, 696–709 (2017).
pubmed: 28965760
pmcid: 5728659
doi: 10.1016/j.cell.2017.08.051
Taguchi, K., Motohashi, H. & Yamamoto, M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16, 123–140 (2011).
pubmed: 21251164
doi: 10.1111/j.1365-2443.2010.01473.x
Wakabayashi, N. et al. Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat. Genet 35, 238–245 (2003).
doi: 10.1038/ng1248
pubmed: 14517554
Murakami, S. et al. NRF2 activation impairs quiescence and bone marrow reconstitution capacity of hematopoietic stem cells. Mol. Cell Biol. 37, e00086–17 (2017).
pubmed: 28674188
pmcid: 5599717
doi: 10.1128/MCB.00086-17
Suzuki, T. et al. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus. Nat. Commun. 8, 14577 (2017).
pubmed: 28233855
pmcid: 5333130
doi: 10.1038/ncomms14577
Poli, V. et al. MYC-driven epigenetic reprogramming favors the onset of tumorigenesis by inducing a stem cell-like state. Nat. Commun. 9, 1024 (2018).
pubmed: 29523784
pmcid: 5844884
doi: 10.1038/s41467-018-03264-2
Sun, Y. et al. HOXA9 reprograms the enhancer landscape to promote leukemogenesis. Cancer Cell 34, 643–658 (2018).
pubmed: 30270123
pmcid: 6179449
doi: 10.1016/j.ccell.2018.08.018
Liu, D. et al. C/EBPβ enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation. Nat. Commun. 9, 1739 (2018).
pubmed: 29712898
pmcid: 5928165
doi: 10.1038/s41467-018-03590-5
de Laval, B. et al. C/EBPβ-dependent epigenetic memory induces trained immunity in hematopoietic stem cells. Cell Stem Cell 26, 793 (2020).
doi: 10.1016/j.stem.2020.03.014
pubmed: 32386557
Choi, E. J. et al. A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer. Oncogene 36, 5285–5295 (2017).
doi: 10.1038/onc.2017.153
pubmed: 28504720
Tsuchida, K. et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic. Biol. Med. 103, 236–247 (2017).
doi: 10.1016/j.freeradbiomed.2016.12.041
pubmed: 28039084
Enomoto, A. et al. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci. 59, 169–177 (2001).
doi: 10.1093/toxsci/59.1.169
pubmed: 11134556
Nezu, M. et al. Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression. Kidney Int. 91, 387–401 (2017).
pubmed: 27789056
doi: 10.1016/j.kint.2016.08.023
Krebs, L. T. et al. Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 37, 139–143 (2003).
doi: 10.1002/gene.10241
pubmed: 14595837
Kofler, N. M., Cuervo, H., Uh, M. K., Murtomäki, A. & Kitajewski, J. Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations. Sci. Rep. 5, 16449 (2015).
pubmed: 26563570
pmcid: 4643246
doi: 10.1038/srep16449
Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011).
pubmed: 21441907
pmcid: 3088773
doi: 10.1038/nature09906
Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature. 518, 317–330 (2015).
Nakato, R. et al. Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells. Epigenetics Chromatin 12, 77 (2019).
pubmed: 31856914
pmcid: 6921469
doi: 10.1186/s13072-019-0319-0
Pabon-Martinez, Y. V. et al. LNA effects on DNA binding and conformation: from single strand to duplex and triplex structures. Sci. Rep. 7, 11043 (2017).
pubmed: 28887512
pmcid: 5591256
doi: 10.1038/s41598-017-09147-8
Okawa, H. et al. Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity. Biochem. Biophys. Res. Commun. 339, 79–88 (2006).
doi: 10.1016/j.bbrc.2005.10.185
pubmed: 16293230
Watai, Y. et al. Subcellular localization and cytoplasmic complex status of endogenous Keap1. Genes Cells 12, 1163–1178 (2007).
pubmed: 17903176
doi: 10.1111/j.1365-2443.2007.01118.x
Trapnell, C. et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511–515 (2010).
pubmed: 20436464
pmcid: 3146043
Katsuoka, F. et al. An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer. Anal. Biochem. 466, 27–29 (2014).
pubmed: 25173513
doi: 10.1016/j.ab.2014.08.015
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
pubmed: 22388286
pmcid: 3322381
doi: 10.1038/nmeth.1923
Li, H. et al. The sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
pubmed: 19505943
pmcid: 19505943
doi: 10.1093/bioinformatics/btp352
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
pubmed: 18798982
pmcid: 2592715
doi: 10.1186/gb-2008-9-9-r137
Consortium, E. P. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).
doi: 10.1038/nature11247
Zerbino, D. R., Johnson, N., Juettemann, T., Wilder, S. P. & Flicek, P. WiggleTools: parallel processing of large collections of genome-wide datasets for visualization and statistical analysis. Bioinformatics 30, 1008–1009 (2014).
pubmed: 24363377
doi: 10.1093/bioinformatics/btt737
Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
pubmed: 21221095
pmcid: 3346182
doi: 10.1038/nbt.1754
Ramírez, F., Dündar, F., Diehl, S., Grüning, B. A. & Manke, T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014).
pubmed: 24799436
pmcid: 4086134
doi: 10.1093/nar/gku365
Quinlan, A. R. BEDTools: the Swiss‐army tool for genome feature analysis. Curr. Protoc. Bioinform. 47, 11–12 (2014).
doi: 10.1002/0471250953.bi1112s47
Favorov, A. et al. Exploring massive, genome scale datasets with the GenometriCorr package. PLoS Comput. Biol. 8, e1002529 (2012).
pubmed: 22693437
pmcid: 3364938
doi: 10.1371/journal.pcbi.1002529