Emerging Insights into Wnt/β-catenin Signaling in Head and Neck Cancer

Head and neck cancer presents primarily as head and neck squamous cell carcinoma (HNSCC), a debilitating malignancy fraught with high morbidity, poor survival rates, and limited treatment options. Mounting evidence indicates that the Wnt/beta-catenin signaling pathway plays important roles in the pathobiology of HNSCC. Wnt/beta-catenin signaling affects multiple cellular processes that endow cancer cells with the ability to maintain and expand immature stem-like phenotypes, proliferate, extend survival, and acquire aggressive characteristics by adopting mesenchymal traits. A central component of canonical Wnt signaling is beta-catenin, which balances its role as a structural component of E-cadherin junctions with its function as a transcriptional coactivator of numerous target genes. Recent genomic characterization of head and neck cancer revealed that while beta-catenin is not frequently mutated in HNSCC, its activity is unchecked by more common mutations in genes encoding upstream regulators of beta-catenin, NOTCH1, FAT1, and AJUBA. Wnt/beta-catenin signaling affects a wide range epigenetic and transcriptional activities, mediated by the interaction of beta-catenin with different transcription factors and transcriptional coactivators and corepressors. Furthermore, Wnt/beta-catenin functions in a network with many signaling and metabolic pathways that modulate its activity. In addition to its effects on tumor epithelia, beta-catenin activity regulates the tumor microenvironment by regulating extracellular matrix remodeling, fibrotic processes, and immune response. These multifunctional oncogenic effects of beta-catenin make it an attractive bona fide target for HNSCC therapy.