Dual mechanism of deltaEF1 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 deltaEF1 in breast cancer. However, the mechanism by which BMP-6 regulates deltaEF1 expression remains unclear. In this study, we confirmed the significant role of BMP-6 in inhibiting MDA-MB-231 migration through decreasing deltaEF1 expression which subsequently relieves deltaEF1-mediated invasion. The inhibitory effect of BMP-6 through deltaEF1 regulation was supported by an inverse correlation of BMP-6/miR-192 and deltaEF1 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 deltaEF1 3'-UTR-luc, validating that deltaEF1 is a target of miR-192. Meanwhile, we also found that BMP-6 acted as a potent transcriptional repressor of the human deltaEF1 promoter. Mutation of the AP-1 binding site on this promoter abolished BMP-6-induced transrepression of deltaEF1. Depletion of BMP-6 expression by RNAi resulted in a significant increase in the promoter activity of deltaEF1. Our study has provided novel findings of a dual mechanism for BMP-6-regulated deltaEF1 expression in breast cancer cells, involving cross-talks between AP-1-mediated transcriptional repression and miRs-mediated translational inhibition.
Yang
Shuang
S
Medical College of Nankai University, 94 Weijin Road, Tianjin 300071, China. yangshuang@nankai.edu.cn
Du
Jun
J
Wang
Zhaoqi
Z
Yan
Jidong
J
Yuan
Wei
W
Zhang
Jie
J
Zhu
Tianhui
T
D020413:3' Untranslated Regions; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004587:Electrophoresis, Agar Gel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
D020413:3' Untranslated Regions; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D015820:Cadherins; D035683:MicroRNAs; D020648:Peptide Elongation Factor 1; D012097:Repressor Proteins