Reduced Expression of METTL3 Promotes Metastasis of Triple-Negative Breast Cancer by m6A Methylation-Mediated COL3A1 Up-Regulation

Abstract

The abnormal m6A modification caused by m6A modulators is a common feature of various tumors; however, little is known about which m6A modulator plays the most important role in triple-negative breast cancer (TNBC). In this study, when analyzing the influence of m6A modulators (<i>METTL3, METTL14, WTAP, FTO</i>, and <i>ALKBH5</i>) on the prognosis of breast cancer, especially in TNBC using several on-line databases, methyltransferase-like 3 (<i>METTL3</i>) was found to have low expression in breast cancer, and was closely associated with short-distance-metastasis-free survival in TNBC. Further investigation showed that knockdown of <i>METTL3</i> could enhance the ability of migration, invasion, and adhesion by decreasing m6A level in TNBC cell lines. Collagen type III alpha 1 chain (<i>COL3A1</i>) was identified and verified as a target gene of <i>METTL3</i>. <i>METTL3</i> could down-regulate the expression of <i>COL3A1</i> by increasing its m6A methylation, ultimately inhibiting the metastasis of TNBC cells. Finally, with immunohistochemistry staining in breast cancer tissues, it was proved that <i>METTL3</i> expression was negatively correlated with <i>COL3A1</i> in TNBC, but not in non-TNBC. This study demonstrated the potential mechanism of m6A modification in metastasis and provided potential targets for treatment in TNBC.