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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / antagonists & inhibitors
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • F-Box Proteins / antagonists & inhibitors
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • Female
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Kelch-Like ECH-Associated Protein 1 / antagonists & inhibitors
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Neoplasm Metastasis
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Transcriptional Activation

Substances

  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • F-Box Proteins
  • FBXO22 protein, human
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • Heme Oxygenase-1