Long non-coding RNA NORAD suppresses erastin-induced ferroptosis in breast cancer by upregulating SLC7A11 via targeting the FUS/NR3C1 axis: experimental studies.

BACKGROUND

Ferroptosis, an iron-dependent cell death, has been widely reported to impede the progression of various malignancies, including breast cancer (BC). Previous evidence has indicated that high expression of non-coding RNA activated by DNA damage (NORAD) is correlated with poor prognosis in BC patients. Nonetheless, it is unclear whether NORAD plays a role in the ferroptosis of BC cells.

METHODS

BC cells were treated with the ferroptosis agonist erastin to induce ferroptosis. Western blotting and quantitative real-time polymerase chain reaction were employed to determine protein and RNA levels, respectively. The cell counting kit-8 assay was used to assess cell viability. Mitochondrial morphology, lipid peroxidation, and intracellular Fe 2+ , malondialdehyde, and glutathione levels were evaluated for ferroptosis. Chromatin immunoprecipitation, luciferase reporter, and RNA immunoprecipitation assays were conducted to explore the molecular mechanism of NORAD. A xenograft mouse model (BALB/c nude) was established to evaluate NORAD's effect on ferroptosis of BC in vivo .

RESULTS

NORAD displayed a high level in human BC tissues and cells. NORAD overexpression and silencing inhibited and facilitated erastin-induced ferroptosis of BC cells, respectively. NORAD upregulated NR3C1 expression via interaction with FUS, and NR3C1 could transcriptionally upregulate solute carrier family 7 member 11 (SLC7A11). Overexpressing SLC7A11 could reverse NORAD silencing-mediated promotion of ferroptosis. NORAD upregulation attenuated the antitumor activity of erastin in tumor-bearing mice.

CONCLUSIONS

NORAD upregulates SLC7A11 via the FUS/NR3C1 axis, thereby suppressing erastin-induced ferroptosis of BC cells.