title: SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition.
abstract: 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.
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hahn
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.forename: Helge
authors.initials: H
authors.lastname: Siemens
authors.forename: Sabine
authors.initials: S
authors.lastname: Hünten
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002465:Cell Movement; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D012097:Repressor Proteins; D012689:Sequence Homology, Nucleic Acid; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53; D014945:Wound Healing
chemical_list: D004268:DNA-Binding Proteins; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; C495901:TP53 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C110951:ZNF148 protein, human; C120370:ZNF281 protein, human