HCC predominantly develops in individuals with chronic hepatic conditions and liver cirrhosis, which is marked by high mortality. This study investigates the functional roles and molecular mechanisms by which FOXP2 modulates HCC progression through ferroptosis. After HCC and normal cells were cultured, the expression of FOXP2, RBM15B, and KDM4C was analyzed using western blot or RT-qPCR. After FOXP2 intervention, cellular metabolic activity was assessed via CCK-8 assay, while replicative capacity was quantified through EdU staining and colony formation assays; key regulators of ferroptosis were analyzed by western blot; iron content and oxidative stress levels were measured. The binding between FOXP2 and RBM15B was investigated through ChIP and dual-luciferase assays. Dual-luciferase reporter assay was used to verify the regulation of RBM15B on KDM4C via m6A modification. MeRIP was utilized to examine m6A enrichment on KDM4C mRNA. ChIP was employed to examine the enrichment of KDM4C and H3K9me3 on SLC7A11 promoters. Combined experiments investigated the role of the RBM15B/KDM4C axis in FOXP2-mediated ferroptosis and HCC cell proliferation. Xenograft models were developed in nude mice to validate the mechanism. FOXP2 expression was downregulated in HCC. FOXP2 overexpression significantly inhibited HCC cell proliferation and promoted ferroptosis. FOXP2 repressed RBM15B expression, suppressed the RBM15B-mediated m6A modification, inhibited KDM4C expression, upregulated H3K9me3 levels, and suppressed SLC7A11 expression, ultimately enhancing ferroptosis. Overexpression of RBM15B or KDM4C attenuated ferroptosis and reversed the suppression of HCC cell growth induced by FOXP2 overexpression. In conclusion, FOXP2 may promote ferroptosis and inhibit cell proliferation in HCC by decreasing SLC7A11 expression via the RBM15B/KDM4C axis in an m6A-dependent manner.
Liu et al. (Mon,) studied this question.