title: AP4 is a mediator of epithelial-mesenchymal transition and metastasis in colorectal cancer.
abstract: The basic helix-loop-helix transcription factor AP4/TFAP4/AP-4 is encoded by a c-MYC target gene and displays up-regulation concomitantly with c-MYC in colorectal cancer (CRC) and numerous other tumor types. Here a genome-wide characterization of AP4 DNA binding and mRNA expression was performed using a combination of microarray, genome-wide chromatin immunoprecipitation, next-generation sequencing, and bioinformatic analyses. Thereby, hundreds of induced and repressed AP4 target genes were identified. Besides many genes involved in the control of proliferation, the AP4 target genes included markers of stemness (LGR5 and CD44) and epithelial-mesenchymal transition (EMT) such as SNAIL, E-cadherin/CDH1, OCLN, VIM, FN1, and the Claudins 1, 4, and 7. Accordingly, activation of AP4 induced EMT and enhanced migration and invasion of CRC cells. Conversely, down-regulation of AP4 resulted in mesenchymal-epithelial transition and inhibited migration and invasion. In addition, AP4 induction was required for EMT, migration, and invasion caused by ectopic expression of c-MYC. Inhibition of AP4 in CRC cells resulted in decreased lung metastasis in mice. Elevated AP4 expression in primary CRC significantly correlated with liver metastasis and poor patient survival. These findings imply AP4 as a new regulator of EMT that contributes to metastatic processes in CRC and presumably other carcinomas.
authors.affiliation: Experimental and Molecular Pathology, Ludwig-Maximilians University of Munich, Germany.
authors.forename: Rene
authors.initials: R
authors.lastname: Jackstadt
authors.forename: Simone
authors.initials: S
authors.lastname: Röh
authors.forename: Jens
authors.initials: J
authors.lastname: Neumann
authors.forename: Peter
authors.initials: P
authors.lastname: Jung
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hoffmann
authors.forename: David
authors.initials: D
authors.lastname: Horst
authors.forename: Christian
authors.initials: C
authors.lastname: Berens
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.forename: Antje
authors.initials: A
authors.lastname: Menssen
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4