SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition

• DOI: 10.1038/emboj.2013.236
• Publication Date: 2013-11-01T15:20:43Z
• Authors: Stefanie Hahn; Rene Jackstadt; Helge Siemens; Sabine Hünten; Heiko Hermeking
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Epithelial-Mesenchymal Transition; Lung Neoplasms; Base Sequence; Molecular Sequence Data; Breast Neoplasms; Mice, SCID; Fibroblasts; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; 03 medical and health sciences; Cell Movement; Mice, Inbred NOD; Case-Control Studies; Animals; Humans; Female; Colorectal Neoplasms; Cells, Cultured

Here, we show that expression of ZNF281/ZBP-99 is controlled by SNAIL and miR-34a/b/c in a coherent feed-forward loop: the epithelial-mesenchymal transition (EMT) inducing factor SNAIL directly induces ZNF281 transcription and represses miR-34a/b/c, thereby alleviating ZNF281 mRNA from direct down-regulation by miR-34. Furthermore, p53 activation resulted in a miR-34a-dependent repression of ZNF281. Ectopic ZNF281 expression in colorectal cancer (CRC) cells induced EMT by directly activating SNAIL, and was associated with increased migration/invasion and enhanced β-catenin activity. Furthermore, ZNF281 induced the stemness markers LGR5 and CD133, and increased sphere formation. Conversely, experimental down-regulation of ZNF281 resulted in mesenchymal-epithelial transition (MET) and inhibition of migration/invasion, sphere formation and lung metastases in mice. Ectopic c-MYC induced ZNF281 protein expression in a SNAIL-dependent manner. Experimental inactivation of ZNF281 prevented EMT induced by c-MYC or SNAIL. In primary CRC samples, expression of ZNF281 increased during tumour progression and correlated with recurrence. Taken together, these results identify ZNF281 as a component of EMT-regulating networks, which contribute to metastasis formation in CRC.