Forkhead box proteins: the tuning forks in cancer development and treatment

Abstract

Introduction Forkhead box (Fox) proteins belong to a superfamily of transcription factors that is characterized by a highly conserved “winged-helix” DNA-binding domain. Following the discovery of the first Fox transcription factor, FoxA, in Drosophila melanogaster , the identification of Fox genes has hitherto revealed at least 19 subclasses in humans (1). Fox proteins hold tight reins on determining cell fate, in particular cell proliferation, differentiation, and survival; thus it is predictable that the deregulation of these proteins has a major impact in the pathogenesis of cancer. Of the Fox proteins, the subfamilies FoxO, FoxM, FoxP, FoxC, and FoxA have been shown to participate in oncogenesis (2). As these Fox proteins recognize similar promoter elements on genomic DNA, they can potentially regulate the expression of overlapping gene targets. However, this chapter will focus on the involvement of the FoxO and FoxM1 proteins in cancer as there is an increasingly well-established and strong relationship between these two groups of Fox proteins through early tumorigenesis to advanced cancer progression and even chemotherapy response. An overview of FoxO and FoxM1 The mammalian FoxO proteins, FoxO1, FoxO3a, FoxO4, and FoxO6, are downstream effectors of the PI3K-Akt (also called PKB) signaling pathway, a signaling cascade that is a focal point for deregulation in most cancers (3). The subcellular localization of FoxO, with the exception of the constitutively nuclear FoxO6, is typically dependent on the phosphorylation of these FoxO proteins by several key kinases, namely Akt/PKB, serum glucocorticord-induced protein kinase (SGK), CK1, IκB kinase (IKKβ), C-Jun N-terminal kinase (JNK), and p38 MAPK (4,5). It is well established that Akt-mediated phosphorylation of FoxO proteins results in cytoplasmic relocation and the consequent inability of these proteins to initiate transcription. Upon translocation to the nucleus, activated FoxO proteins are able to control cell fate by transcriptionally activating or repressing target genes by binding to the DNA of consensus sequences, and by interacting with other transcriptional co-activators such as p300/CREB-binding protein (CBP).