LncRNA MEG3/CTCF-CXCR4 axis functions in the regulation of breast cancer cell migration

Abstract

Loss or decreased expression of lncRNA MEG3 is a frequent event in the progression of many different malignancies. Overexpression of MEG3 in breast cancer cell lines MCF7 or MDA-MB-231 prevented cell migration, whereas depletion of MEG3 in human mammary epithelial cell line MCF10A strikingly promoted cell migration. As RNA-protein interactions are vital for RNA to function, RNP assembled on MEG3 in vivo was purified using affinity purification followed by mass spectrometry, which revealed ∼600 proteins with the potential to interact with MEG3. Bioinformatic analysis on RNA-seq data from MCF7 with MEG3 overexpression and MCF10A with MEG3 depletion led to the identification of CXCR4 as the major downstream mediator negatively regulated by MEG3 that facilitated breast cancer cell migration. In addition, the chromatin regulator CTCF emerged as the MEG3-binding protein that might regulate CXCR4 expression after comparison of proteins presenting in MEG3 lncRNP to ChIP-seq data and GPSAdb data of CXCR4. Further evidence was provided to show CTCF upregulated the expression of CXCR4 at transcriptional level, whereas co-expression of MEG3 with CTCF abolished transcriptional activation of CXCR4. Overall, our study pinpoints the importance of MEG3/CTCF-CXCR4 axis in regulating migration of breast cancer cells and provides novel insight into the mechanism of lncRNA MEG3 in cancer development.