WWOX gene is located in FRA16D, the highly affected chromosomal fragile site. Its tumor suppressor activity has been proposed on a basis of numerous genomic alterations reported in chromosome 16q23.3-24.1 locus. WWOX is affected in many cancers, showing as high as 80% loss of heterozygosity in breast tumors. Unlike most tumor suppressors impairing of both alleles of WWOX is very rare. Despite cellular and animal models information on a WWOX role in cancer tissue is limited and sometimes confusing. This review summarizes information on WWOX in human tumors.

The brain is the most functionally organized structure of all organs. It manages behavior, perception and higher cognitive functions. The WWOX gene is non-classical tumor suppressor gene, which has been shown to have an impact on proliferation, apoptosis and migration processes. Moreover, genetic aberrations in WWOX induce severe neuropathological phenotypes in humans and rodents. The aim of the present study was to investigate in detail the impact of WWOX on human neural progenitor cell (hNPC) maintenance and how depletion of WWOX disturbs signaling pathways playing a pivotal role in neuronal differentiation and central nervous system (CNS) organogenesis. hNPC with a silenced WWOX gene exhibited lowered mitochondrial redox potential, enhanced adhesion to fibronectin and extracellular matrix protein mixture, downregulation of MMP2/9 expression and impaired 3D growth. Global transcriptome analysis using cap analysis of gene expression (CAGE) found that WWOX downregulation significantly changes the expression of multiple genes engaged in cytoskeleton organization, adhesion, cell signaling and chromatin remodeling. The massive changes in gene expression caused by WWOX silencing may strongly affect the differentiation and migration of neurons in organogenesis, brain injury, cancerogenesis or neurodifferentiation. WWOX gene appears to be an important regulator of neural tissue architecture and function.

Recent reports indicate that the hypoxia-induced factor (HIF1α) and the Warburg effect play an initiating role in glucotoxicity, which underlies disorders in metabolic diseases. WWOX has been identified as a HIF1α regulator. WWOX downregulation leads to an increased expression of HIF1α target genes encoding glucose transporters and glycolysis’ enzymes. It has been proven in the normoglycemic mice cells and in gestational diabetes patients. The aim of the study was to determine WWOX’s role in glucose metabolism regulation in hyperglycemia and hypoxia to confirm its importance in the development of metabolic disorders. For this purpose, the WWOX gene was silenced in human normal fibroblasts, and then cells were cultured under different sugar and oxygen levels. Thereafter, it was investigated how WWOX silencing alters the genes and proteins expression profile of glucose transporters and glycolysis pathway enzymes, and their activity. In normoxia normoglycemia, higher glycolysis genes expression, their activity, and the lactate concentration were observed in WWOX KO fibroblasts in comparison to control cells. In normoxia hyperglycemia, it was observed a decrease of insulin-dependent glucose uptake and a further increase of lactate. It likely intensifies hyperglycemia condition, which deepen the glucose toxic effect. Then, in hypoxia hyperglycemia, WWOX KO caused weaker glucose uptake and elevated lactate production. In conclusion, the WWOX/HIF1A axis downregulation alters glucose metabolism and probably predispose to metabolic disorders.

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Introduction WWOX gene is a tumour suppressor which loss of expression is demonstrated in many cancers. WWOX is involved in the regulation of glucose metabolism by interaction with HIF1a. WWOX knockdown regulates the metabolic switch from oxidative phosphorylation to aerobic glycolysis in breast cancer MCF7 cell line. This metabolic reprograming called the Warburg effect enhances glycolysis to generate energy over oxidative phosphorylation in aerobic conditions. We considered that aerobic glycolysis can be upregulated via changes in WWOX expression in case of women with gestational diabetes mellitus (GDM). We hypothesised that WWOX has a function in regulating glucose metabolism in GDM. Literature indicates that GDM may be associated with increased risk of breast cancer. Material and methods We analysed expression level of WWOX, HIF1A, glucose transporters SLC2A1, SLC2A4 and glycolytic genes HK2, PFK1, PKM2, LDHA by RT-qPCR in GDM and NGT blood samples. The expression of same genes, we analysed in normal/tumour pair of breast tissue from GEO database (GSE109169). The results, we referred to expression level of these genes in MCF7 and MCF7 sh WWOX cell line obtained by Abu-Remaileh et. al. Results and discussions Relative expression level of WWOX was lower in case of GDM than NGT. Opposite result we observed for HIF1A. Moreover, WWOX/HIF1A ratio is significantly lower in GDM than NGT. The increased level of HIF1A in GDM group is further associated with higher expression of glucose transporters and glycolytic genes. In GDM we observed negative correlation between WWOX/ HIF1A ratio and HIF1A, SLC2A1 as well as HK2, PFK and PKM2. WWOX knockout in MCF7 leads to increasing of HIF1a target glycolytic genes. Similar to GDM, WWOX expression level is lower and HIF1A is higher in breast cancer in comparison to normal breast tissue, which gives statistically lower WWOX/HIF1A ratio. Expression level of SLC2A1, HK2, PKM2, LDHA in breast cancer are higher than in normal. Conclusion We found elevated WWOX and HIF1A expression level, enhanced glycolysis, reduced WWOX/HIF1A ratio in GDM. Our results suggest that WWOX is responsible for Warburg effect occurrence in GDM via regulation of HIF1A, as like in breast cancer. Therefore, a hypothesis can be formed that elevated risk of breast cancer in diabetes mellitus patients could be associated with systemic WWOX function insufficiency.