Potassium channel tetramerization domain-containing 10 exerts a tumor suppressive function in breast cancer by destabilizing SLC7A11 to induce ferroptosis

Potassium channel tetramerization domain-containing 10 (KCTD10) plays a crucial role in the progression of various tumors. However, comprehensive studies on the involvement of KCTD10 in breast cancer are still lacking. This research aims to elucidate the potential roles and mechanisms of KCTD10 in breast cancer. Reduced KCTD10 expression was observed in breast cancer and was associated with poorer overall survival. Upregulation of KCTD10 resulted in a significant decline in cell growth and proliferation. Notably, KCTD10 overexpression induced ferroptosis, as evidenced by increased cell death, elevated ferrous ion levels, and enhanced lipid peroxidation. The anti-tumor effects mediated by KCTD10 elevation were significantly counteracted by ferroptosis inhibitors, while KCTD10 knockdown resulted in increased resistance to this form of cell death. KCTD10 overexpression reduced the protein levels of SLC7A11, a process reversible by proteasome inhibitors. In KCTD10 knockdown cells, the degradation rate of SLC7A11 protein was significantly decreased. Notably, restoring SLC7A11 expression in KCTD10-overexpressing cells significantly counteracted the tumor-suppressive effects of KCTD10. Tumor-bearing mouse models demonstrated that KCTD10-overexpressing cells exhibited significantly reduced tumor formation capabilities, accompanied by increased ferroptosis levels in tumor tissues. Collectively, KCTD10 exerts a vital anti-cancer role in breast cancer by promoting the ubiquitin-proteasome degradation of SLC7A11, which reduces GSH synthesis, limits the inhibition of lipid peroxidation, and ultimately triggers ferroptosis. By providing new insights into the molecular mechanisms underlying breast cancer pathogenesis, this research identifies KCTD10 as a valuable therapeutic target and suggests that gene therapies aimed at restoring its expression may offer promising avenues for breast cancer treatment.