Transcription Factor AP4 Mediates Cell Fate Decisions: To Divide, Age, or Die

SIMPLE SUMMARY: Here, we review the literature on Activating Enhancer-Binding Protein 4 (AP4)/transcription factor AP4 (TFAP4) function and regulation and its role in cancer. Elevated expression of AP4 was detected in tumors of various organs and is associated with poor patient survival. AP4 is encoded by a Myc target gene and mediates cell fate decisions by regulating multiple processes, such as cell proliferation, epithelial-mesenchymal transition, stemness, apoptosis, and cellular senescence. Thereby, AP4 may be critical for tumor initiation and progression. In this review article, we summarize published evidence showing how AP4 functions as a transcriptional activator and repressor of a plethora of direct target genes in various physiological and pathological conditions. We also highlight the complex interactions of AP4 with c-Myc, N-Myc, p53, lncRNAs, and miRNAs in feed-back loops, which control AP4 levels and mediate AP4 functions. In the future, a better understanding of AP4 may contribute to improved prognosis and therapy of cancer. ABSTRACT: Activating Enhancer-Binding Protein 4 (AP4)/transcription factor AP4 (TFAP4) is a basic-helix-loop-helix-leucine-zipper transcription factor that was first identified as a protein bound to SV40 promoters more than 30 years ago. Almost 15 years later, AP4 was characterized as a target of the c-Myc transcription factor, which is the product of a prototypic oncogene that is activated in the majority of tumors. Interestingly, AP4 seems to represent a central hub downstream of c-Myc and N-Myc that mediates some of their functions, such as proliferation and epithelial-mesenchymal transition (EMT). Elevated AP4 expression is associated with progression of cancer and poor patient prognosis in multiple tumor types. Deletion of AP4 in mice points to roles of AP4 in the control of stemness, tumor initiation and adaptive immunity. Interestingly, ex vivo AP4 inactivation results in increased DNA damage, senescence, and apoptosis, which may be caused by defective cell cycle progression. Here, we will summarize the roles of AP4 as a transcriptional repressor and activator of target genes and the contribution of protein and non-coding RNAs encoded by these genes, in regulating the above mentioned processes. In addition, proteins interacting with or regulating AP4 and the cellular signaling pathways altered after AP4 dysregulation in tumor cells will be discussed.