Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1
Open accessAbstract
Approximately 30% of human lung cancers acquire mutations in either Keap1 or Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which controls oxidative homeostasis. Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival and metastasis in lung cancer patients. We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
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Mutations to NRF2 and its regulator KEAP1 have been found in cancer cells, supporting the supposition that antioxidant genes are pivotal in tumor progression.
“In this regard, mutations to NRF2 and its regulator KEAP1 have been found in cancer cells, supporting the supposition that antioxidant genes are pivotal in tumor progression59–62.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [62]
Accumulated BACH1 is involved in the mechanism promoting metastasis.
“Accumulated BACH1 is involved in the mechanism promoting metastasis.”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Lignitto et al. 2019
In response to oxidative stress, Nrf2 accumulated and stabilizes a pro-metastatic transcription factor BACH1 by inducing HO-1.
“It has been reported that in response to oxidative stress, Nrf2 accumulated and stabilizes a pro-metastatic transcription factor BACH1 by inducing HO-1.”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Lignitto et al. 2019
Oxidative stress suppressed by antioxidants can increase the stability of BACH1 and promote its accumulation in lung cancer cells.
“This recent important work suggests that oxidative stress suppressed by antioxidants can in turn increase the stability of BACH1 and promote its accumulation in lung cancer cells.”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Lignitto et al. 2019
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The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging
Yu, C., & Xiao, J.-H. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6635460 · Cited by 537 · see citing works
The aging lung: Physiology, disease, and immunity
Schneider, J. L., Rowe, J. H., Garcia-de-Alba, C., Kim, C. F., Sharpe, A. H., & Haigis, M. C. (2021) · Cell · doi:10.1016/j.cell.2021.03.005 · Cited by 500 · see citing works
Thirty years of NRF2: advances and therapeutic challenges.
Zhang, D. D. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01145-0 · Cited by 282 · see citing works
LeBoeuf, S. E., Wu, W. L., Karakousi, T. R., Karadal, B., Jackson, S. R., Davidson, S. M., Wong, K.-K., Koralov, S. B., Sayin, V. I., & Papagiannakopoulos, T. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.012 · Cited by 150 · see citing works
Self-citationFunctional genomics in vivo reveal metabolic dependencies of pancreatic cancer cells
Zhu, X. G., Chudnovskiy, A., Baudrier, L., Prizer, B., Liu, Y., Ostendorf, B. N., Yamaguchi, N., Arab, A., Tavora, B., Timson, R., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.017 · Cited by 130 · see citing works
Precision Redox: The Key for Antioxidant Pharmacology
Meng, J., Lv, Z., Zhang, Y., Wang, Y., Qiao, X., Sun, C., Chen, Y., Guo, M., Han, W., Ye, A., et al. (2021) · Antioxidants & Redox Signaling · doi:10.1089/ars.2020.8212 · Cited by 122 · see citing works
Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation
Gong, M., Li, Y., Ye, X., Zhang, L., Wang, Z., Xu, X., Shen, Y., & Zheng, C. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00568-z · Cited by 86 · see citing works
Metabolic features of cancer cells in NRF2 addiction status
Okazaki, K., Papagiannakopoulos, T., & Motohashi, H. (2020) · Biophysical Reviews · doi:10.1007/s12551-020-00659-8 · Cited by 57 · see citing works
Self-citationDistinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
DeBlasi, J. M., Falzone, A., Caldwell, S., Prieto-Farigua, N., Prigge, J. R., Schmidt, E. E., Chio, I. I. C., Karreth, F. A., & DeNicola, G. M. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3848 · Cited by 49 · see citing works
“Preclinical genetically engineered mouse models (GEMMs) have advanced our understanding of the role 59 of NRF2 in lung tumorigenesis (23, 27-37).”
Influential
- Authors
- Lignitto, L., LeBoeuf, S. E., Homer, H., Jiang, S., Askenazi, M., Karakousi, T. R., Pass, H. I., Bhutkar, A. J., Tsirigos, A., Ueberheide, B., Sayin, V. I., Papagiannakopoulos, T., & Pagano, M.
- Affiliations
- NYU Langone Health (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Papagiannakopoulos, Thales
- Pagano, Michele
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 178
- Issue
- 2
- Pages
- 316-329.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6625921
- OpenAlex
- W2955964880
- Cited by
- 573
- References
- 76
- Citations by year
- 2026: 43 · 2025: 72 · 2024: 66 · 2023: 100 · 2022: 81 · 2021: 106 · 2020: 86 · 2019: 17
- FWCI
- 24.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- American-Italian Cancer Foundation
- American Cancer Society (RSG-17-200-01\u2013TBE)
- National Institutes of Health (R01GM57587, R01CA76584, R37CA222504, R01CA227649, T32HL007151, S10OD018338, K22CA201088, S10OD01058, S10OD010582)
- European Commission
- Associazione Italiana per la Ricerca sul Cancro
- Marie Curie
- Wenner-Gren Foundation
- Stanford Genome Technology Center
- Svenska Läkaresällskapet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- Nrf2, lung cancer metastasis, BACH1, heme, FBXO22, Keap1, heme oxygenase-1, protein degradation, ubiquitin ligase, oxidative homeostasis, metastasis treatment
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Animals, Cell Movement, Female, Humans, Lung Neoplasms, Male, Mice, Inbred C57BL, Neoplasm Metastasis, Transcriptional Activation, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, RNA Interference, RNA, Small Interfering, F-Box Proteins, Cell Line, Tumor, Basic-Leucine Zipper Transcription Factors, NF-E2-Related Factor 2, Mice, Heme Oxygenase-1, Kaplan-Meier Estimate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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