FOXA2 controls the antioxidant response in FH-deficient cells independent of NRF2

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 the activation of an antioxidant response by KEAP1 succination and nuclear translocation of the transcription factor NRF2. The activation of the antioxidant response is key for cellular survival in FH-deficient cells, yet the extent to which chromatin remodelling shapes the antioxidant response is currently unknown. Here, we explored the global effects of FH loss and fumarate accumulation on the chromatin landscape to identify transcription factor networks involved in the highly remodelled chromatin landscape of FH-deficient cells. We identify FOXA2 as a key transcription factor which enables the survival of FH-deficient cells by directly regulating antioxidant response genes and subsequent metabolic rewiring. Moreover, we also find that FOXA2 regulates antioxidant genes independent of the canonical antioxidant regulator NRF2. The identification of FOXA2 as an antioxidant regulator provides new insights into the molecular mechanisms behind cell responses to fumarate accumulation, and potentially provides new avenues for therapeutic intervention for HLRCC. ### Competing Interest Statement The authors have declared no competing interest.