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

Abstract

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/β-catenin signaling pathway plays important roles in the pathobiology of HNSCC. Wnt/β-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 β-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 β-catenin is not frequently mutated in HNSCC, its activity is unchecked by more common mutations in genes encoding upstream regulators of β-catenin, NOTCH1, FAT1, and AJUBA. Wnt/β-catenin signaling affects a wide range epigenetic and transcriptional activities, mediated by the interaction of β-catenin with different transcription factors and transcriptional coactivators and corepressors. Furthermore, Wnt/β-catenin functions in a network with many signaling and metabolic pathways that modulate its activity. In addition to its effects on tumor epithelia, β-catenin activity regulates the tumor microenvironment by regulating extracellular matrix remodeling, fibrotic processes, and immune response. These multifunctional oncogenic effects of β-catenin make it an attractive bona fide target for HNSCC therapy.

Keywords: cancer microenvironment; carcinoma; epigenomics; signal transduction; stem cells; therapeutics.

Figure 1.

Schematic of the Wnt/β-catenin signaling cascade. Wnt signaling inactive: in the absence of Wnt ligand, cytoplasmic β-catenin is maintained at low levels by the destruction complex composed of the scaffold protein Axin in complex with APC, GSK3β, and CK1α that phosphorylates the N-terminal region of β-catenin and targets it for proteosomal degradation via βTrCP E3 ubiquitin ligase. Wnt signaling active: the binding of Wnt ligand to the Fzd receptor-Lrp6/5 coreceptor complex inactivates the destruction complex and leads to the accumulation of cytoplasmic β-catenin and its subsequent translocation to the nucleus, where it interacts with TCF-LEF transcription factor and activates target genes. In the nucleus, β-catenin partners with different transcriptional coactivators, such as CBP and p300, through which it affects distinct subsets of genes. Additional effectors of Wnt/β-catenin signaling include R-spondins and their receptors LGR4/5, which potentiate Wnt signaling, and RNF43/ZRNF3 E3 ubiquitin ligases, which antagonize it. In addition, E-cadherin functions as a tumor suppressor that interferes with Wnt/β-catenin activity.

Figure 2.

Structure of β-catenin facilitates interactions with different nuclear partners. The β-catenin protein is comprised of 12 armadillo repeats (numbered boxes), an amino-terminal domain (NTD) and carboxy-terminal domain (CTD), and the conserved helix C as the flexible component of CTD. (A) At least 4 different transcription factors (purple bars) and 3 transcriptional inhibitors (gray bars) have been shown to interact with β-catenin and mapped to its specific structural domains. (B) Transcriptional coactivators bind to defined regions of β-catenin to mediate its diverse signaling outcomes (green bars).

Figure 3.

Targeting the β-catenin/cAMP-responsive element binding protein (CBP) axis in head and neck squamous cell carcinoma (HNSCC). Inhibition of the β-catenin–CBP interaction is proposed to abrogate subpopulations of tumor cancer stem cells (CSCs) and promote epithelial cell differentiation. In addition, reduced β-catenin/CBP activity is expected to induce antitumor immunity by depleting exhausted T cells and decreasing the frequency of immature heterogeneous cells of the myeloid lineage, or myeloid-derived suppressor cells (MDSCs) involved in immune evasion.