Nrf2 activation promotes lung cancer metastasis by inhibiting the degradation of Bach1
Authors: Luca Lignitto, Sarah E. LeBoeuf, Harrison Homer, Shaowen Jiang, Manor Askenazi, Triantafyllia R. Karakousi, Harvey I. Pass, Arjun J. Bhutkar, Aristotelis Tsirigos, Beatrix Ueberheide, Volkan I. Sayin, Thales Papagiannakopoulos, Michele Pagano
Summary:
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-dependentmanner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependentmanner. Human metastatic lung cancer displays 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-mediateddegradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
Source: Cell, 2019
Summary:
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-dependentmanner. Pharmacological inhibition of Ho1 suppresses metastasis in a Fbxo22-dependentmanner. Human metastatic lung cancer displays 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-mediateddegradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
Source: Cell, 2019