The link between NRF2 and BACH1 in redox pathways and radiation responses

Radiation (RT) is effective in treating many types of cancers by inducing oxidative stress through the generation of reactive oxygen species (ROS) that result in DNA damage. However, both tumour intrinsic mechanisms for suppressing ROS as well as the hypoxic microenvironment reduce the efficacy of RT. While significant efforts are being pursued to enhance radiation efficacy, our lab will focus on RT-induced ROS that kill cells by inducing ferroptosis. Ferroptosis has recently been described as a non-apoptotic form of cell death dependent on iron and lipid peroxides that contributes to radiation-induced cell death. Studies suggest that the ferroptosis pathway is independent of DSBs and that enhancing ROS induced lipid peroxidation can promote cell killing as well as overcome the problem of tumour radioresistance mediated by intrinsic radical scavengers. NRF2 is a transcription factor playing a major role in protecting cells from oxidative damage. When bound to small MAF proteins, NRF2 transcriptionally activate its target genes through binding to the antioxidative response element (ARE) on their promoter regions. BACH1 is a transcriptional repressor of these antioxidative genes through the competition with NRF2 for ARE and small MAF bindings. In the recent study suggests that NRF2 promotes BACH1-mediated lung cancer metastasis through BACH1 stabilisation. Therefore, there seems to be a tight regulation of NRF2 and BACH1 in promoting cancer through competition or cooperation. In our proposed study we will determine how NRF2 and BACH1 play together in radiation responses while focusing on redox pathways, ferroptosis, and DNA damage.