Kindlin 2 promotes breast cancer invasion via epigenetic silencing of the microRNA200 gene family

Abstract

Kindlin 2, as a focal adhesion protein, controls integrin activation and regulates Wnt signaling in an integrin-binding independent manner. However, the association of Kindlin 2 with cancer-related microRNAs is unknown. Here, we report that Kindlin 2 markedly downregulates the expression of miR-200 family by inducing CpG island hypermethylation. Mechanistically, Kindlin 2 forms a complex with DNMT3A in the cell nucleus and the two proteins co-occupy the promoter of miRNA-200b. Functionally, repression of miR-200b is required for Kindlin 2-induced breast cancer cell invasion and tumor formation. Our data indicate that Kindlin 2 plays a novel role in epigenetic repression of miR-200 family, a mechanism that promotes breast cancer invasion. What's new? Recent studies have implicated Kindlin 2, a focal adhesion protein, in boosting tumor progression. This study investigated the association of Kindlin 2 with microRNAs (miRNAs), which are frequently altered in cancer. The authors showed that Kindlin 2 forms a complex with DNA methyltransferase 3A, and this complex then blocks the miR-200b promoter. MicroRNAs in the miR-200 family function as tumor repressors, and their loss is crucial for cell invasion and tumor progression. These new results demonstrate for the first time that Kindlin 2 promotes breast cancer invasion by working together with DNA methyltransferase 3A to stifle miR-200b expression. Copyright © 2013 UICC.