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

ABSTRACT

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.