Disease relevance of WWOX

• We conclude that WWOX alterations occur in a significant fraction of lung cancers and may contribute to the pathogenesis of non-small cell lung cancer [1].
• WWOX and FHIT promoter methylation is detected in tissue adjacent to breast cancer and WWOX exon 1 MSP distinguishes breast cancer DNA from DNA of adjacent and normal tissue [2].
• 1. To investigate the role of the WWOX gene in the development of gastric carcinoma, we examined a large series of primary adenocarcinomas and nine gastric cancer cell lines for the expression of Wwox [3].
• A FHIT/WWOX MLPA assay was designed, applied and validated in five esophageal squamous cell carcinoma ESCC, cell lines established in South Africa where this cancer is of high prevalence [4].
• A DNA blot study showed that WWOX and FHIT genes were deleted in 2 of 18 cases with primary acute leukemias; both genes were not expressed in the 2 cases [5].
• WWOX expression was strongly associated with tumor histology (P=1.1x10(-5)) and histologic grade (P=0.0081): the percentage of cases with absent/strongly reduced WWOX expression was higher in squamous cell carcinomas and in poorly differentiated tumors [6].

High impact information on WWOX

• The WWOX gene was expressed in lung cancer cell lines through recombinant adenovirus (Ad) infection (Ad-WWOX), and through a drug [ponasterone A, (ponA)]-inducible system [7].
• This study confirms that WWOX is a tumor suppressor gene and is highly effective in preventing growth of lung cancer xenografts, whether introduced through viral infection or by induction of a silent WWOX transgene [7].
• After WWOX restoration in vitro, endogenous Wwox protein-negative cell lines (A549, H460, and H1299) underwent apoptosis through activation of the intrinsic apoptotic caspase cascade in A549 and H460 cells [7].
• We have examined the tumor suppressor function of WWOX in preclinical lung cancer models [7].
• We demonstrate the homozygous deletion of WWOX exons from ovarian cancer cells and three different tumor cell lines [8].

Biological context of WWOX

• The FOR (WWOX) gene spans FRA16D and encodes a partner of p53 that also has a role in apoptosis [9].
• Transcripts missing WWOX exons were detected in 7 primary tumors (7 of 27; 25.9%) and 5 of 8 cell lines [1].
• In addition, loss of heterozygosity at the WWOX locus was observed in 10 primary tumors (10 of 27; 37.0%) [1].
• WW domain-containing oxidoreductase WOX1, also named WWOX or FOR, undergoes Tyr33 phosphorylation at its first N-terminal WW domain and subsequent nuclear translocation in response to sex steroid hormones and stress stimuli [10].
• Differential patterns of WWOX and FHIT methylation were observed in neoplastic vs adjacent non-neoplastic tissues, suggesting that targeted MSP amplification could be useful in following treatment or prevention protocols [2].

Anatomical context of WWOX

• Previously untested 53 cancer cell lines were screened for deletions within the FOR/WWOX gene [9].
• Coexpression of WWOX and ErbB-4 in HeLa cells followed by treatment with TPA results in the retention of ErbB-4 in the cytoplasm [11].
• The results from our study indicate that WWOX is preferentially highly expressed in secretory epithelial cells of reproductive, endocrine and exocrine organs, as well as in ductal epithelial cells from specific segments of the urinary system [12].
• Due to the potential role of WWOX in sex-steroid metabolism, whole sections from hormonally regulated organs like breast, ovaries, testes and prostate were also analyzed [12].
• Interestingly, we also observed significant WWOX protein expression in various cell types of neural origin including neurons, ependymal cells and astrocytes [12].

Associations of WWOX with chemical compounds

• Methylation analysis showed that site-specific promoter hypermethylation was detected in 2 cell lines (22%) and treatment with the demethylating agent 5-aza-2'-deoxycytidine demonstrated an increase in the expression of WWOX [13].
• Our biochemical study reveals that ezrin directly binds to the first WW domain of WWOX via its C-terminal tyrosine-containing polyproline sequence (470)PPPPPPVY(477) [14].
• Estrogen and androgen stimulate phosphorylation and nuclear translocation of WWOX, although binding of WWOX to these sex hormones is unknown [15].
• Conformationally altered hyaluronan restricts complement classical pathway activation by binding to C1q, C1r, C1s, C2, C5 and C9, and suppresses WOX1 expression in prostate DU145 cells [16].

Physical interactions of WWOX

• The p53/WOX1 complex translocated to the mitochondria and further to the nuclei to mediate apoptosis [17].
• WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins [18].

Regulatory relationships of WWOX

• In addition, our results show that interaction of WWOX and ErbB-4 suppresses transcriptional coactivation of CTF by YAP in a dose-dependent manner [11].
• WOX1 induced apoptosis synergistically with p53 [17].

Other interactions of WWOX

• Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer [2].
• Effect of exogenous E2F-1 on the expression of common chromosome fragile site genes, FHIT and WWOX [19].
• Aberration or absence of WWOX expression recently was detected in primary hematopoietic malignancies [20].
• In summary, our data indicate that WWOX antagonizes the function of YAP by competing for interaction with ErbB-4 and other targets and thus affect its transcriptional activity [11].
• Mutational analyses further demonstrate that tyrosine(477) is essential for the ezrin-WWOX interaction [14].

Analytical, diagnostic and therapeutic context of WWOX

• EXPERIMENTAL DESIGN: Loss of heterozygosity, reverse-transcription-PCR, and immunohistochemistry were used to assess the role of WWOX in stomach cancer [3].
• Western blot analysis showed a significant reduction of the WWOX protein in all of the cell lines [13].
• Real-time reverse transcription PCR revealed a significant reduction of WWOX expression in all of the cell lines and in 6 primary tumors (40%) [13].
• The long arm of chromosome 16 was identified as being frequently associated with structural abnormalities in multiple neoplasias, that led us to focus attention on the detailed genetic dissection of this region resulting in the cloning of the putative tumor suppressor gene, WWOX (WW domain containing Oxidoreductase) [21].
• Furthermore, by RT-PCR, no abnormal transcripts of this WWOX/FOR gene was detected in nine HCC cell lines [22].

References