Hypoxic stabilization of RIPOR3 mRNA via METTL3-mediated mA methylation drives breast cancer progression and metastasis.

Dysregulated N-methyladenosine (mA) modification has been associated with breast cancer pathogenesis. Hypoxia which characterizes solid tumors is known to reprogram the mA epitranscriptome, but the underlying mechanisms of how this process contributes to breast cancer progression remain poorly understood. Through integrative analyses of mA-RIP sequencing and RNA sequencing databases, we reveal a cluster of mRNAs with upregulated mA methylation and expression under hypoxia, that are enriched by many oncogenic pathways, including PI3K-Akt signaling. Furthermore, we identify the mRNA, RIPOR3, as a target of METTL3-mediated mA methylation in response to hypoxia. We find that mA methylation stabilizes RIPOR3, increasing its protein expression in a METTL3 catalytic activity-dependent manner, and consequently driving breast tumor growth and metastasis. RIPOR3 is found to be overexpressed in breast cancer cell lines and tumor tissues from breast cancer patients, in whom elevated RIPOR3 is associated with a worse prognosis. Mechanistically, we show that RIPOR3 interacts with EGFR and is essential for the PI3K-Akt pathway activation. In conclusion, we identify RIPOR3 as a hypoxia-stabilized oncogenic driver via METTL3-mediated mA methylation, thus provide a potential therapeutic target for breast cancer.