METTL16 epigenetically enhances GPX4 expression via m6A modification to promote breast cancer progression by inhibiting ferroptosis

Abstract

Breast cancer is malignant cancer that severely threatens the life quality of female patients. N6-methyladenosine (m6A) is a prevalent modification of RNA. METTL16 is an important methyltransferase. This work aims to study the role of METTL16 in breast cancer cell death. The expression of METTL16 in clinical breast cancer specimens was analyzed by qPCR assay. The in vitro and in vivo breast cancer cell proliferation was measured by CCK8, colony formation, and xenograft mouse model. Cell ferroptosis was assessed by measuring the accumulation of iron, Fe2+, and lipid ROS. The mechanistic study was performed by RNA degradation, qPCR, and Western blotting assay. METTL16 was overexpressed in tumor tissues from breast cancer patients compared with the para-tumor tissues. Knockdown of METTL16 suppressed in vitro cell proliferation and in vivo tumor growth of breast cancer cells. Meanwhile, METTL16 silencing led to elevated intracellular levels of iron, Fe2+, and lipid ROS, indicating the incidence of ferroptosis. Furthermore, siMETTL16 decreased m6A methylation and enhanced the degradation of GPX4 RNA. METTL16-regulated m6A methylation of GPX4 stimulates proliferation and suppresses ferroptosis of breast cancer cells. Therefore, we concluded that METTL16 epigenetically enhanced GPX4 expression via m6A modification to promote breast cancer progression by inhibiting ferroptosis.