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Cell. 2019 Jul 11;178(2):316-329.e18. doi: 10.1016/j.cell.2019.06.003. Epub 2019 Jun 27.

Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1.

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
2
Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
3
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Biomedical Hosting LLC, 33 Lewis Avenue, Arlington, MA 02474, USA.
4
Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Cardiothoracic Surgery, New York University School of Medicine, New York, NY 10016, USA.
5
Koch Institute for Integrative Cancer Research, MIT, 77 Massachusetts Ave. Building 76, Cambridge, MA 02139, USA.
6
Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: papagt01@nyumc.org.
7
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: michele.pagano@nyumc.org.

Abstract

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.

KEYWORDS:

Bach1; CRL complexes; F-box proteins; Fbxo22; Heme; Ho1 inhibitor; Keap1; Nrf2; cullin-RING ubiquitin ligase; lung cancer; metastasis; ubiquitin

PMID:
31257023
PMCID:
PMC6625921
[Available on 2020-07-11]
DOI:
10.1016/j.cell.2019.06.003

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