FOXA2 controls the anti-oxidant response in FH-deficient cells
Connor Rogerson,
Marco Sciacovelli,
Lucas A. Maddalena,
Andromachi Pouikli,
Marc Segarra-Mondejar,
Lorea Valcarcel-Jimenez,
Christina Schmidt,
Ming Yang,
Elena Ivanova,
Joshua Kent,
Ariane Mora,
Danya Cheeseman,
Jason S. Carroll,
Gavin Kelsey,
Christian Frezza
Affiliations
Connor Rogerson
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK
Marco Sciacovelli
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK
Lucas A. Maddalena
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK
Andromachi Pouikli
University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Marc Segarra-Mondejar
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Lorea Valcarcel-Jimenez
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Christina Schmidt
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Ming Yang
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD)
Elena Ivanova
Epigenetics Programme, Babraham Institute, Cambridge, UK
Joshua Kent
CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
Ariane Mora
School of Chemistry and Molecular Biosciences, University of Queensland, Molecular Biosciences Building 76, St Lucia, QLD 4072, Australia
Danya Cheeseman
CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
Jason S. Carroll
CRUK Cambridge Institute, University of Cambridge, Cambridge, UK
Gavin Kelsey
Epigenetics Programme, Babraham Institute, Cambridge, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge, UK; Wellcome-MRC Institute of Metabolic Science - Metabolic Research Laboratories, Cambridge, UK
Christian Frezza
MRC Cancer Unit, University of Cambridge, Hutchison MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK; University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD); University of Cologne, Faculty of Medicine and University Hospital Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD); Corresponding author
Summary: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a cancer syndrome caused by inactivating germline mutations in fumarate hydratase (FH) and subsequent accumulation of fumarate. Fumarate accumulation leads to profound epigenetic changes and the activation of an anti-oxidant response via nuclear translocation of the transcription factor NRF2. The extent to which chromatin remodeling shapes this anti-oxidant response is currently unknown. Here, we explored the effects of FH loss on the chromatin landscape to identify transcription factor networks involved in the remodeled chromatin landscape of FH-deficient cells. We identify FOXA2 as a key transcription factor that regulates anti-oxidant response genes and subsequent metabolic rewiring cooperating without direct interaction with the anti-oxidant regulator NRF2. The identification of FOXA2 as an anti-oxidant regulator provides additional insights into the molecular mechanisms behind cell responses to fumarate accumulation and potentially provides further avenues for therapeutic intervention for HLRCC.
