Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells

Abstract

WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic-and CNS-associated functions and their underlying molecular basis.The WWOX gene initially became a research target due to its localization in a region of considerable chromosomal instability (16q23.2), at common fragile site (CFS) 3 FRA16D, which immediately marked it as a possible tumor suppressor gene (TSG) (1, 2). Inactivation of TSGs at CFSs has long been known as a hallmark of cancer (3). CFSs are evolutionarily conserved genomic regions that are sensitive to replicative stress (4). In 2010, Beroukhim et al. (5) demonstrated that deletion of TSGs spanning CFSs is among the most significant driver events in cancer. Although highly recombinogenic, CFSs are rarely involved in oncogenic activation, suggesting that CFSs are mainly hot spots for inactivation of tumor suppressors (3). A number of animal studies were conducted on WWOX, and in keeping with the above paradigm, many insights were gained into WWOX's association with cancer development (reviewed elsewhere (6 -10)). However, a few surprising results led the research in other unanticipated directions, linking WWOX to regulation of metabolic function, as well as neuronal development (Fig. 1). These animal model studies were complemented by studies on the cellular and molecular levels, modeling WWOX structure and identifying its potential binding partners, thus generating a comprehensive functional model of WWOX activity.This review sketches out how our view of WWOX has evolved over the years, with emphasis on the recent findings that link WWOX to metabolic regulation and CNS homeostasis. We begin with an overview of the original WWOX animal model studies, followed by an outline of subsequent WWOX research performed at the cellular and molecular levels. We review potential WWOX binding partners and their associated cellular pathways. We further define WWOX structure and architecture, expounding its behavior in the context of its two tandem WW domains and expansive short-chain dehydrogenase/reductase (SDR) region. Taken together, we generate a functional model of WWOX that highlights the versatility of this protein and suggests possible new directions for further study of WWOX's complex nature. Animal Model...

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

“…Several WWOX mutations have been reported in patients characterized as having intellectual disability, epilepsy, developmental delay, and/or neurological manifestations of ataxia (AbdelSalam et al 2014;Mallaret et al 2014;Mignot et al 2015;Ben-Salem et al 2015;Valduga et al 2015;Tabarki et al 2015). The WWOX-associated phenotype displays a wide range of phenotypic abnormalities which might be related to the nature of mutations; point mutations (such as p.P47T, p.P47R, p.G372R) are usually associated with milder phenotypes than those associated with nonsense mutations (such as p.R54*, p.K297*, p.W335*) or partial/complete deletions (Abu-Remaileh et al 2015). Nonsense or null mutations exhibited severe phenotype including progressive microcephaly, severe early onset spasticity, infantile epileptic encephalopathy, optic atrophy, failure to thrive, and premature death or abortion (Abdel-Salam et al 2014, Ben-Salem et al 2015, Tabarki et al 2015, while missense mutations in our patients and others cause a milder phenotype with no progressive microcephaly, no spasticity or spasticity with exaggerated reflexes (Mallaret et al 2014).…”

Role of WW Domain-containing Oxidoreductase WWOX in Driving T Cell Acute Lymphoblastic Leukemia Maturation

“…We have previously reported the presence of WWOX and p53 in the mitochondria (22,39,44). In addition, WWOX is involved in mitochondrial respiration and metabolism (45,46). By co-immunoprecipitation, yeast two-hybrid analysis, timelapse FRET microscopy, and expression of cloned plasmid vectors, we deciphered how the component proteins in the complex interact with each other and how the action contributes to MOLT-4 maturation.…”

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

“…Human WWOX gene has 1.1 million bases and is located on a chromosomal common fragile site 16q23 or FRA16D . High frequency of loss of heterozygosity (LOH) of WWOX gene at approximately 30–50% levels has been shown in many types of cancer cells (Aqeilan and Croce, 2007; Chang et al, 2007; Del Mare et al, 2009; Gardenswartz and Aqeilan, 2014; Abu-Remaileh et al, 2015; Chang, 2015; Chang et al, 2015; Richards et al, 2015; Schrock and Huebner, 2015). Mutation of WWOX gene in breast cancer occurs frequently at exons 4–9 (Ekizoglu et al, 2012).…”

“…Loss of WWOX gene expression can be due to hypermethylation of gene promoter (Iliopoulos et al, 2005; Chang et al, 2010; Gardenswartz and Aqeilan, 2014). When cytosolic WWOX protein relocates to the nucleus under stress conditions, WWOX is able to maintain genomic stability by controlling ATM activation and DNA damage response (Abu-Odeh et al, 2014; Abu-Remaileh et al, 2015). Most recently, WWOX-mediated suppression of cancer cell growth has been established in Drosophila (O'Keefe et al, 2015).…”

“…When WWOX undergoes Lys63-linked ubiquitination at Lys274 by E3 ubiquitin ligase ITCH, it relocates to the nucleus and enhances cell death (Abu-Odeh et al, 2014; Abu-Remaileh et al, 2015). In addition, vesicle trafficking protein TRAPPC6A binds WWOX and acts as a carrier for WWOX to undergo nuclear accumulation (Chang and Chang, 2015).…”