KIAA1429/VIRMA promotes breast cancer progression by m⁶ A-dependent cytosolic HAS2 stabilization

N⁶ -methyladenosine (m⁶ A), the most abundant internal modification in eukaryotic mRNA, plays important roles in many physiological and pathological processes, including the development and progression of cancer. RNA modification by m⁶ A is regulated by methyltransferases, demethylases, and m⁶ A-binding proteins that function in large part by regulating mRNA expression and function. Here, we investigate the expression of m⁶ A regulatory proteins in breast cancer. We find that expression of KIAA1429/VIRMA, a component of the m⁶ A methyltransferase complex, is upregulated in breast cancer tissue and correlates positively with poor survival. KIAA1429/VIRMA is mislocalized to the cytosol of breast cancer tissues and cell lines, and shRNA-mediated knockdown inhibits breast cancer cell proliferation, migration, and invasion. Mechanistically, KIAA1429/VIRMA is shown to bind to the m⁶ A-dependent RNA-binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), leading to recruitment and stabilization of m⁶ A-modified hyaluronan synthase 2 (HAS2) mRNA. HAS2 mRNA and KIAA1429/VIRMA mRNA levels correlate positively in breast cancer tissues, suggesting that the KIAA1429/VIRMA-IGF2BP3-HAS2 axis promotes breast cancer growth and contributes to poor prognosis.