cDTL contributes to breast cancer progression through regulating redox homeostasis via affecting the function of system xc.

Abstract

Ferroptosis is a new type of cell death caused by redox imbalance mediated by iron-dependent lipid peroxidation, which is intimately linked to human disease. Circular RNA, characterized by covalently closed loop structure, has attracted much attention due to its involvement in various biological functions. However, little is known about the role of circRNA in ferroptosis. In this study, we identified cDTL (a circular RNA derived from DTL gene) as a ferroptosis-related circRNA. cDTL expression was remarkably elevated by ferroptotic stress. Knockdown of cDTL significantly inhibited breast cancer cell growth both in vitro and in vivo through promoting ferroptosis. Mechanistically, cDTL directly bound to NRF2 and BCLAF1 in the nucleus and cytoplasm, respectively, resulting in transcriptional activation and mRNA stability of SLC7A11 (the core subunit of system Xc^-), thereby repressing ferroptosis via activating GSH/GPX4 axis. Moreover, cDTL was identified as a direct transcriptional target of Myc, a well-known protooncogene that is highly activated in breast cancer. More importantly, cDTL was overexpressed in human breast cancer tissues, which was associated with dismal progression-free survival and poor differentiation. In conclusion, our data suggest that cDTL is a novel regulator of ferroptosis, targeting cDTL may be a potential therapeutic strategy for breast cancer.