KIAA1429 / VIRMA promotes breast cancer progression by m 6 A ‐dependent cytosolic HAS2 stabilization

Abstract

N 6 ‐methyladenosine (m 6 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 m 6 A is regulated by methyltransferases, demethylases, and m 6 A‐binding proteins that function in large part by regulating mRNA expression and function. Here, we investigate the expression of m 6 A regulatory proteins in breast cancer. We find that expression of KIAA1429/VIRMA, a component of the m 6 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 m 6 A‐dependent RNA‐binding protein insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3), leading to recruitment and stabilization of m 6 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. image The m 6 A methyltransferase complex component KIAA1429/VIRMA is upregulated and mislocalized to the cytosol in breast cancer tissues and cell lines. A KIAA1429/VIRMA–IGF2BP3–HAS2 axis promotes breast cancer growth and might contribute to poor prognosis. Expression and cytosolic distribution of KIAA1429/VIRMA are elevated in breast cancer tissue and cell lines. KIAA1429/VIRMA depletion reduces HAS2 mRNA m 6 A levels, RNA stability, and expression. Cytosolic KIAA1429/VIRMA interacts with m 6 A binder IGF2BP3 and enhances HAS2 mRNA expression. HAS2 plays an essential role for KIAA1429/VIRMA‐mediated breast cancer cell proliferation and migration.