Differentiation modifies Bach1 dependent regulation of HO-1 expression and increases sensitivity to oxidative stress in neuroblastoma cells

Neuronal adaptation to oxidative stress is crucial to prevent degenerative diseases. The role of the Nrf2/HO-1 system in cell response to hydrogen peroxide (H 2 O 2 ) has been investigated using SH-SY5Y neuroblastoma cells as undifferentiated or after differentiation with all-trans retinoic acid (ATRA). We showed that undifferentiated cells resisted to oxidative stimulus and up-regulated HO-1 which was responsible for their survival, since its silencing decreased viability in cells exposed to H 2 O 2 . On the contrary, in ATRA-treated cells the viability decreased in response to increasing concentration of H 2 O 2 and HO-1 was not induced. However, bilirubin supplementation restores cell viability, underlining the role of HO-1-derived bilirubin in cell resistance to oxidative stress. Investigating the mechanisms of HO-1 induction, we showed that in undifferentiated cells the nuclear level of Bach1, repressor of HO-1 transcription, decreased as well as its binding to the promoter of HO-1. In the same condition, Nrf2 binding to the same DNA region increased. Yet, in differentiated cells Bach1 nuclear level was not modified by the exposure to H 2 O 2 as well as its binding to HO-1 promoter and, as a consequence, the binding of Nrf2 to HO-1 promoter was not modified by H 2 O 2 . In conclusion, our findings highlight the role of Bach1/HO-1/bilirubin in neuronal response to oxidative stress.