Novel LncRNA LINC02936 Suppresses Ferroptosis and Promotes Tumor Progression by Interacting with SIX1/CP Axis in Endometrial Cancer.

ABSTRACT

Endometrial cancer (EC) is a prevalent gynecological malignancy, and metabolic disorders are among its most significant risk factors. Abnormal iron metabolism is associated with the progression of cancer malignancy. Nevertheless, the involvement of iron metabolism in the EC remains uncertain. Ceruloplasmin (CP) functions as a multicopper oxidase and ferroxidase, playing a crucial role in maintaining the metabolic balance between copper and iron. Prior research has demonstrated that the dysregulated expression of CP has important clinical implications in EC. However, ​the specific underlying molecular mechanisms remains uncertain. This research examined the impact of CP on the malignant advancement of EC by suppressing ferroptosis. Next, we explored the possibility that Long non-coding RNA (lncRNA) LINC02936/SIX1/CP axis may be a key pathway for inhibiting ferroptosis and promoting cancer progression in EC. Mechanistically, SIX1 modulates the expression of CP, whereas LINC02936 interacts with SIX1 and recruits SIX1 to the CP promoter, leading to upregulation of CP, inhibition of ferroptosis, and promotion of EC progression. Administration of a small peptide cloud block the LINC02936-SIX1 interaction, thereby inhibits EC progression by promoting ferroptosis. Altogether, this is the first report on the lncRNA regulation of ferroptosis in EC. Our research enhances the knowledge of the lncRNA-mediated regulation of ferroptosis in EC progression and indicates the potential therapeutic significance of the LINC02936/SIX1/CP axis in treating EC.