The second most common fragile site in the human genome is the FRA16D region where the WWOX gene is localized which codes for a 414 amino acid protein. WWOX is a member of the WW-domain containing protein family consisting of 2000 members. It is a partner of several transcription factors and therefore functions in multiple physiological and pathological processes such as cell growth, differentiation and tumor suppression. Genomic alterations within the WWOX gene and its differential expression have been found in a variety of human tumors. Although some transcription factor partners of the WWOX protein have been identified its exact mechanism of action is not known. A recent study indicated that WWOX inhibits the Wnt/β-catenin pathway by preventing the nuclear import of the Dishvelled (Dvl) proteins. Dvl proteins are the main down-stream target of Wnt receptors (Frizzled- FRZ). Following binding of Wnt to its receptor alterations of β-catenin degradation lead to β-catenin accumulation in the cytoplasm. Accumulated β-catenin translocates into the nucleus and activates expression of target genes. Therefore dysregulation of the Wnt signaling pathway is a key oncogenic mechanism in many different cancers. Although Wnt and its receptor FRZ have been analyzed in head and neck squamous cell carcinoma (HNSCC) the intracellular components of the pathway have not been investigated. This is the first study in the literature reporting a role for β-catenin and Dvl mRNA level alterations in HNSCC. In our previous study we have identified that the WWOX gene is inactivated in HNSCC as a result of genetic and epigenetic alterations. To identify the mechanism of action of WWOX in HNSCC in this study we investigated its expression in association with Dvl-1, Dvl-2, Dvl-3 and β-catenin expression in 98 HNSCC samples. We observed down-regulation of the WWOX mRNA in 73.5% of the HNSCC tumor samples compared to their non-cancerous counterparts. Up-regulation of the Dvl-1, Dvl-2, Dvl-3 and β-catenin mRNAs were detected in 32.7%, 36%, 38.8% and 24.5% of the same tumor samples, respectively. We also detected a statistically significant correlation between the WWOX gene expression and mRNA levels of the intracellular components of the Wnt pathway genes. Our results indicate that WWOX acts as a tumor suppressor in the HNSCC development and progression by inhibiting the expression of the Dvl proteins.

Citation Format: Ayse Nur Buyru, Asuman Celebi, Betul Seyhan. The role of WWOX in HNSCC through Wnt/beta-catenin pathway [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B33.