Northwestern Events Calendar

Dec
5
2019

BMG Seminar: Nrf2 activation promotes lung cancer metastasis by inhibiting the Fbxo22-mediated degradation of Bach1 -Michele Pagano, MD

When: Thursday, December 5, 2019
10:00 AM - 11:00 AM  

Where: Simpson Querrey Biomedical Research Center, SQBRC Auditorium, 303 E. Superior Street, Chicago, IL 60611 map it

Audience: Faculty/Staff - Student - Post Docs/Docs - Graduate Students

Contact: Vanessa Hughes   312.503.5229

Group: Biochemistry & Molecular Genetics Seminar Series

Category: Lectures & Meetings

Description:

About 30% of lung adenocarcinomas (LUADs) increase the transcription of antioxidant genes to maintain oxidative homeostasis. This increase is made possible by mutations that stabilize Nrf2, the master transcriptional regulator of the cell’s antioxidant program. These mutations are associated with an aggressive cancer phenotype and either directly target Nfe2L2 (encoding Nrf2) or inactivate Nrf2’s negative regulator, Keap1. Keap1 is a substrate receptor of a CRL3 ubiquitin ligase complex that, in physiological conditions, constitutively targets Nrf2 for degradation. We asked whether LUADs with Keap1 mutations are more aggressive than LUADs harboring wild-type Keap1 due to an increased metastatic burden, and by which mechanism. We found that stabilization of Nrf2 in LUAD activates a pathway that in turn stabilizes Bach1, a transcription factor that controls the expression of a plethora of pro-metastatic genes. Mechanistically, mutations that stabilize Nrf2 drive the Nrf2-mediated induction of heme oxygenase 1 (Ho1), an enzyme responsible for heme catabolism. We also found that heme promotes the interaction of Bach1 with CRL1Fbxo22. Therefore, increased heme catabolism leads to a decrease in free heme, reducing the CRL1Fbxo22-mediated degradation of Bach1. Thus, in normal cells, either Nrf2 is low and Bach1 is high (under unstressed conditions) or Nrf2 is high and Bach1 is low (upon oxidative stress). Instead, LUAD cells paradoxically display high levels of both Nrf2 and Bach1, thus promoting cell survival and inducing cell migration, respectively. We extensively validated our mechanistic results in mouse models of LUAD, as well as in samples of LUAD patients. We propose that: 1) Nrf2 induces lung cancer metastases by reducing heme- and Fbxo22-mediated degradation of Bach1, which in turn activates the transcription of pro-metastatic genes; and 2) drugs targeting the heme pathway represent a promising strategy to block metastasis in LUAD patients. Moreover, we suggest that Ho1 and Bach1 could be used as LUAD biomarkers to improve the design of precision medicine approaches and clinical trials, and to monitor the response to therapy.

Michele Pagano, MD
Chair, Department of Biochemistry and Molecular Pharmacology
May Ellen and Gerald Jay Ritter Professor of Oncology, Department of Biochemistry and Molecular Pharmacology
New York University School of Medicine
Howard Hughes Medical Institute Investigator



 

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