cancers Review Transcription Factor AP4 Mediates Cell Fate Decisions: To Divide, Age, or Die Matthew Man-Kin Wong 1,2 , Sancy Mary Joyson 3,4 , Heiko Hermeking 5,6,7, * and Sung Kay Chiu 3,8, *   Citation: Wong, M.M.-K.; Joyson, S.M.; Hermeking, H.; Chiu, S.K. Transcription Factor AP4 Mediates Cell Fate Decisions: To Divide, Age, or Die. Cancers 2021, 13, 676. https://doi.org/10.3390/ cancers13040676 Academic Editor: Didier Picard Received: 18 January 2021 Accepted: 3 February 2021 Published: 8 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; mwong043@uottawa.ca 2 Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada 3 Department of Biological Sciences, Xi’an Jiaotong-Liverpool University, Suzhou 215123, China; S.Joyson@liverpool.ac.uk 4 Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK 5 Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, 80337 Munich, Germany 6 German Cancer Consortium (DKTK), Partner site Munich, 80336 Munich, Germany 7 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 8 Faculty of Health and Life Sciences, University of Liverpool, Brownlow Hill, Liverpool L69 7TX, UK * Correspondence: heiko.hermeking@med.uni-muenchen.de (H.H.); david.chiu@xjtlu.edu.cn (S.K.C.); Tel.: +49-89-2180-73685 (H.H.); +86-512-8188-3224 (S.K.C.) 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 summa- rize 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. Keywords: transcription factor AP4; cell proliferation; apoptosis; EMT; tumorigenesis Cancers 2021, 13, 676. https://doi.org/10.3390/cancers13040676 https://www.mdpi.com/journal/cancers