WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies

Abstract

WWOX was cloned as a putative tumor suppressor gene mapping to chromosomal fragile site FRA16D. Deletions affecting WWOX accompanied by loss of expression are frequent in various epithelial cancers. Translocations and deletions affecting WWOX are also common in multiple myeloma and are associated with worse prognosis. Metanalysis of gene expression datasets demonstrates that low WWOX expression is significantly associated with shorter relapse-free survival in ovarian and breast cancer patients. Although somatic mutations affecting WWOX are not frequent, analysis of TCGA tumor datasets led to identifying 44 novel mutations in various tumor types. The highest frequencies of mutations were found in head and neck cancers, uterine and gastric adenocarcinomas. Mouse models of gene ablation led us to conclude that Wwox does not behave as a highly penetrant, classical tumor suppressor gene since its deletion is not tumorigenic in most models and its role is more likely to be of relevance in tumor progression rather than in initiation. Analysis of signaling pathways associated with WWOX expression confirmed previous in vivo and in vitro observations linking WWOX function with the TGFβ/SMAD and WNT signaling pathways and with specific metabolic processes. Supporting these conclusions recently we demonstrated that indeed WWOX behaves as a modulator of TGFβ/SMAD signaling by binding and sequestering SMAD3 in the cytoplasmic compartment. As a consequence progressive loss of WWOX expression in advanced breast cancer would contribute to the pro-metastatic effects resulting from TGFβ/SMAD3 hyperactive signaling in breast cancer. Recently, GWAS and resequencing studies have linked the WWOX locus with familial dyslipidemias and metabolic syndrome related traits. Indeed, gene expression studies in liver conditional KO mice confirmed an association between WWOX expression and lipid metabolism. Finally, very recently the first human pedigrees with probands carrying homozygous germline loss of function WWOX mutations have been identified. These patients are characterized by severe CNS related pathology that includes epilepsy, ataxia and mental retardation. In summary, WWOX is a highly conserved and tightly regulated gene throughout evolution and when defective or deregulated the consequences are important and deleterious as demonstrated by its association not only with poor prognosis in cancer but also with other important human pathologies such as metabolic syndrome and CNS related pathologic conditions.

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

“…Furthermore, as mentioned above, somatic genomic rearrangements involving WWOX is one of the three most common cytogenetic findings in a variety of cancers3 34 and WWOX encompasses the FRA16D common fragile site located in its largest intron (intron 8 is 0.8 Mb long, NM016373.2). Common fragile sites are large regions of profound genomic instability found in all individuals, which are usually located in large introns and prone to breakage upon replication stress.…”

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

“…Notably, null mutations of WWOX/Wwox gene in humans and animals lead to severe neural diseases (e.g., microcephaly, seizure, ataxia, etc. ), growth retardation, metabolic disorders, developmental delay, and early death (Aldaz et al, 2014; Chang et al, 2014; Alkhateeb et al, 2016; Elsaadany et al, 2016). Nevertheless, no spontaneous cancer formation has been seen in the newborns, arguing whether WWOX is a real tumor suppressor.…”

“…And, this leads to a general belief that WWOX sequesters prosurvival transcription factors in the cytoplasm to block cancer growth (Chang et al, 2001, 2003, 2005, 2007; Aqeilan et al, 2004; Aqeilan and Croce, 2007; Aldaz et al, 2014; Abu-Remaileh et al, 2015). Inducible WWOX sequesters SMAD3 in the cytoplasm and inhibits its transcriptional function (Ferguson et al, 2013).…”

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

“…Some of these reports described early onset death of patients, as shown in the Wwox null mice [17, 90, 91], precluding adult tumor analysis. Other reports described adult epileptic patients homozygous for mutant WWOX but with no sign of tumor development, suggesting that other hits and/or mutations might be required for cancer to develop [87, 105]. It remains unknown whether these neuronal defects result from impaired DDR function of WWOX or whether patients harboring WWOX null mutations are more sensitive to tumor development over their life span.…”