Abstract
The Wnt/beta-catenin signaling pathway is increasingly recognized for its roles in head and neck cancer, a devastating malignancy that presents primarily as head and neck squamous cell carcinoma (HNSCC). Wnt/beta-catenin signaling impacts multiple cellular processes that endow cancer cells with the ability to maintain and expand immature stemlike phenotypes and proliferate, extend cancer cell survival, and promote aggressive characteristics resulting from loss of epithelial features and adoption of mesenchymal traits. A central component of the canonical Wnt signaling pathway is beta-catenin, which balances a role as a structural component of cadherin junctions with function as a transcriptional coactivator of numerous target genes. While beta-catenin is not frequently mutated in HNSCC, its activity is enhanced by some of the more common HNSCC mutations in NOTCH1, FAT1, and AJUBA. The impact of beta-catenin on a wide range of epigenetic, transcriptional, and cellular processes is mediated by its interaction with numerous transcription factors, as well as with a multitude of transcriptional coactivators and corepressors, in a cell- and tissue-context-dependent manner. In addition, intrinsic beta-catenin activity plays important roles in the tumor microenvironment and thus regulates extracellular matrix remodeling and immune response. Lastly, Wnt/beta-catenin signaling collaborates with, and converges on, other signaling and metabolic pathways and cellular processes that modulate outputs of its activity. Unraveling the complex circuitries of Wnt/beta-catenin signaling will facilitate its effective targeting for HNSCC therapy.