Overcoming BET-inhibitor JQ1 resistance in aggressive non-small cell lung cancer by inducing ferroptosis via inhibition of the BRD2-FTH1 axis.

Recent studies emphasize the involvement of the nuclear H ferritin subunit (FTH1; also known as ferritin heavy chain) in DNA protection from oxidative damage and transcriptional regulation. Bromodomain and extra-terminal domain (BET) proteins act as epigenome readers for transcriptional regulation. Among them, the role of bromodomain-containing protein 2 (BRD2) in non-small cell lung carcinoma (NSCLC) remains unclear. Moreover, the clinical utilization of BET bromodomain inhibition is severely limited by different sensitivities among NSCLC subtypes. This study provides the first evidence of nuclear BRD2-FTH1 functional interplay. Nuclear FTH1 is associated with BRD2, not bromodomain-containing protein 4 (BRD4), in a panel of NSCLC cell lines and affects BRD2 protein stability only in more aggressive types of NSCLC cells. In addition, the protective function of FTH1 was abrogated in FTH1-silenced cells that are resistant to synthetic BET bromodomain inhibitor JQ1 (a thieno-triazolo-1,4-diazepine) but not in JQ1-sensitive cells, leading to an increase in mortality. Then, the potential mechanism by which the combination of JQ1 with FTH1 silencing induces cell death was explored. The results show that ferroptosis is involved in the anticancer effect of JQ1 upon FTH1 silencing only in JQ1-insensitive cells. Moreover, the expression of ferroptosis-associated genes glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2) was downregulated under JQ1 treatment only after FTH1 silencing, indicating that the BRD2 inhibition due to the co-treatment could regulate the expression of ferroptosis-associated genes. In summary, for the first time, our data suggest that FTH1 silencing may serve as an effective anti-tumor strategy to enhance the activity of JQ1, acting to overcome the chemotherapy resistance in more aggressive NSCLCs.