Linc01060 suppresses ferroptosis by downregulating SPOP-mediated c-Myc degradation in glioma

Abstract

Background: Ferroptosis is a type of regulated cell death induced by iron-dependent lipid peroxidation that plays an essential role in the pathogenesis of various diseases, including cancer. Previously, we reported that long non-coding RNA (lncRNA) Linc01060 regulates aggressive phenotype and aerobic glycolysis in glioma cells. However, the precise functions and underlying molecular mechanisms of Linc01060 in ferroptosis remain unknown.Methods: We explored the upstream regulatory mechanism of Linc01060 expression in hypoxic conditions in glioma cells. The expression and prognostic significance of Linc01060 in patients with glioma was analyzed using data from the Cancer Genome Atlas. The role of Linc01060 in regulating ferroptosis in glioma was evaluated both in vitro and in vivo. Linc01060 expression in clinical glioma specimens was evaluated by fluorescence in situ hybridization, immunofluorescence, and immunohistochemistry.Results: Linc01060 expression was found to be transactivated by hypoxia inducible factor-1 alpha. A strong correlation was found between Linc01060 expression and ferroptosis biomarkers, suggesting that Linc01060 is a negative regulator of ferroptosis. Linc01060 rescued erastin-induced ferroptosis and promoted tumor progression in glioma cells both in vitro and in vivo. Speckle-type POZ protein (SPOP), an E3 ligase of c-Myc, was identified as the target protein of Linc01060. We found that mechanistically Linc01060 competitively binds to SPOP, downregulating SPOP-mediated c-Myc degradation, and thereby decreasing the sensitivity of glioma cells to ferroptosis.Conclusion: Linc01060 suppresses ferroptosis by modulating the SPOP/c-Myc axis in glioma cells. Our results suggest that targeting Linc01060 is a potential strategy for the treatment of tumors.