Journal Article

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

Lai, Ming‐Tsung, Chiang, An‐Jen, Korla, Praveen Kumar, Gracilla, Daniel E., Liou, Wen‐Shiung, Sheu, Jim Jinn‐Chyuan

2020

Overview

A novel cancer gene MB21D2, a known intracellular cadherin binder, was found to harbor Q311E recurrent mutation and to be overexpressed in head and neck cancer (HNSCC). Wild‐type MB21D2 and its mutant form mediate pro‐oncogenic activities and promote EMT. Blockage of RAS could be used as a strategy for treating cancer with MB21D2 overexpression or mutation, particularly for tumors resistant to DNA‐damaging drugs. 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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: 1-Phosphatidylinositol 3-kinase / Animals / Apoptosis - genetics / Cadherins / Cadherins - metabolism / cadherin‐binding gene / Carcinogenesis - genetics / Carcinogenesis - pathology / Cell adhesion / Cell adhesion & migration / Cell Cycle Checkpoints - genetics / Cell Line, Tumor / Cell migration / Cell Movement - genetics / Cell Proliferation - genetics / Cervical carcinoma / Embryogenesis / Epithelial cells / Epithelial-Mesenchymal Transition - genetics / Esophageal cancer / Esophagus / Gene expression / Gene Expression Regulation, Neoplastic / Genomes / Glutamic acid / Glutamine / Head & neck cancer / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - pathology / Humans / Inositol / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / K-Ras protein / Kinases / Lung carcinoma / MB21D2 / Mice, Nude / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Mutation hot spots / Neck / Neoplasm Proteins - metabolism / Organogenesis / overexpression / Phenotype / Phenotypes / Protein Binding / Q311E recurrent mutation / recurrent Q311E mutation / Sarcoma / Signal Transduction / Spheroids, Cellular - metabolism / Spheroids, Cellular - pathology / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - genetics / Squamous Cell Carcinoma of Head and Neck - pathology / Tumor Stem Cell Assay / Tumors / Up-Regulation - genetics / Xenograft Model Antitumor Assays