Dual mechanism of δEF1 expression regulated by bone morphogenetic protein-6 in breast cancer

The metastatic nature of breast cancer has been well recognized, yet the mechanisms through which breast cancer cells acquire their invasive properties have not been clearly elucidated. Our previous study indicates that BMP-6 restores E-cadherin-mediated EMT through repressing δEF1 in breast cancer. However, the mechanism by which BMP-6 regulates δEF1 expression remains unclear. In this study, we confirmed the significant role of BMP-6 in inhibiting MDA-MB-231 migration through decreasing δEF1 expression which subsequently relieves δEF1-mediated invasion. The inhibitory effect of BMP-6 through δEF1 regulation was supported by an inverse correlation of BMP-6/miR-192 and δEF1 expressions observed in both MDA-MB-231 and MCF-7 cells and clinical tumor specimens. Moreover, BMP-6 treatment or miR-192 transfection decreased the reporter activity of the δEF1 3′-UTR-luc, validating that δEF1 is a target of miR-192. Meanwhile, we also found that BMP-6 acted as a potent transcriptional repressor of the human δEF1 promoter. Mutation of the AP-1 binding site on this promoter abolished BMP-6-induced transrepression of δEF1. Depletion of BMP-6 expression by RNAi resulted in a significant increase in the promoter activity of δEF1. Our study has provided novel findings of a dual mechanism for BMP-6-regulated δEF1 expression in breast cancer cells, involving cross-talks between AP-1-mediated transcriptional repression and miRs-mediated translational inhibition.