The methyltransferase METTL3 promotes the progression of breast cancer cells via regulating EGF m6A modification.

Abstract

Ranking second out of new cancer cases, breast cancer (BRCA) is the leading cause of cancerous death among women globally. Methyltransferase-like 3 (METTL3), as the well-known N6‑methyladenosine (m6A) "writer" with catalytic function, regulates cancer progression through specific downstream targets, but its interplay with epidermal growth factor (EGF) signaling in BRCA is poorly defined. Here, we depict a METTL3-m6A-EGF axis in BRCA, where BRCA cell properties were affected by METTL3 through m6A-dependent expression of EGF. We observed the correlation between METTL3 expression in BRCA tissues and negative prognosis through bioinformatics analysis and RT-qPCR. In vitro lentiviral-mediated METTL3 knockdown suppressed proliferation and migration, while the in vivo tumor formation experiment in nude mice validated the tumor-promoting effect of METTL3. Hematoxylin-eosin staining and immunohistochemistry also showed the tumor-promoting effect of METTL3. Mechanistically, METTL3 stabilized EGF mRNA via m6A modification, as evidenced by MeRIP-qPCR and Western blotting. Notably, METTL3 maintains EGF/EGFR signaling, and its overexpression leads to insensitivity to gefitinib and adriamycin. We naturally conclude that METTL3 is a central epigenetic regulator of EGF-driven BRCA progression, providing a rationale for targeting METTL3 to overcome chemotherapeutic resistance.