Overexpression of wild type or a Q311E mutant MB21D2 promotes a pro‐oncogenic phenotype in HNSCC

Cadherin‐mediated cell–cell contacts regulated by intracellular binders play critical roles in tissue homeostasis and tumorigenesis. Here, we screened mutational profiles of 312 annotated genes involved in cadherin binding in human squamous cell carcinomas and found MB21D2 to carry a unique recurrent Q311E mutation. MB21D2 overexpression was also frequently found in head and neck cancer (HNSCC) and was associated with poor clinical outcomes. Cell‐based characterizations revealed pro‐oncogenic roles for MB21D2 wild‐type (WT) and its Q311E mutant (Q311E) in cell proliferation, colony formation, sphere growth, and migration/invasion by promoting epithelial–mesenchymal transition. Conversely, MB21D2 knockdown in MB21D2‐overexpressing cells resulted in cell growth arrest and apoptosis. Xenograft tumor models with Q311E‐expressing cells formed larger and more aggressive lesions, compared to models with WT‐MB21D2‐expressing cells or an empty vector. Transcriptome and protein interactome analyses revealed enrichment of KRAS signaling by MB21D2 expression. Immunoblotting confirmed RAS elevation, along with upregulation/phosphorylation of PI3K, AKT, and CREB. Blocking RAS signaling in MB21D2‐expressing cells by manumycin significantly reduced cell growth and survival. Our study thus defined RAS signaling‐dependent pro‐oncogenic roles for MB21D2 overexpression and Q311E MB21D2 expression in HNSCC development.