Molecular mechanisms of HO-1 up-regulation in neuroblastoma cell response to oxidative stress

Heme oxygenase 1 (HO-1) up-regulation drives cell adaptation to different stressors. Previous works from our lab have shown that HO-1 plays a crucial role in neuroblastoma cells (NB) response to oxidative stress (OS), but also demonstrated that sensitivity to OS increases after retinoic acid-induced NB-differentiation. In this study, we evaluated the involvement of the molecular mechanisms of HO-1 induction in NB cell response to OS, analyzing its main activator Nrf2 and its main repressor Bach1. We showed that retinoic acid-differentiated NB cells are more susceptible to OS as they reduce the ability to up-regulate HO-1. We demonstrated that Bach1 displacement from HO-1 promoter in undifferentiated cells enables the binding of Nrf2, while in differentiated cells, Bach1 displacement was impaired preventing Nrf2 binding and HO-1 induction. Furthermore, we considered the role played by miRNA494, which could be involved in Bach1 post-transcriptional regulation. Preliminary data showed that miRNA494 is down-regulated in differentiated cells and that its inhibition in undifferentiated cells increases sensitivity to OS. In conclusion, this study highlights the role of Bach1 in the regulation of HO-1 in NB cell response to OS.