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FOXA2 controls the anti-oxidant response in FH-deficient cells.

Abstract
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.
AuthorsConnor 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
JournalCell reports (Cell Rep) Vol. 42 Issue 7 Pg. 112751 (07 25 2023) ISSN: 2211-1247 [Electronic] United States
PMID37405921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Chemical References
  • Fumarate Hydratase
  • Antioxidants
  • NF-E2-Related Factor 2
  • Chromatin
  • FOXA2 protein, human
  • Hepatocyte Nuclear Factor 3-beta
Topics
  • Female
  • Humans
  • Fumarate Hydratase (genetics)
  • Antioxidants
  • NF-E2-Related Factor 2 (genetics)
  • Leiomyomatosis (genetics)
  • Uterine Neoplasms (genetics)
  • Skin Neoplasms (genetics)
  • Neoplastic Syndromes, Hereditary (genetics)
  • Chromatin
  • Kidney Neoplasms (genetics)
  • Carcinoma, Renal Cell (genetics)
  • Hepatocyte Nuclear Factor 3-beta (genetics)

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