Delta Np63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and several molecular pathways that underlie the molecular tumorigenesis of HNSCC have been identified. Among them, amplification or overexpression of Delta Np63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a Delta Np63-dependent transcriptional program able to regulate the metabolism and the signaling of hyaluronic acid (HA), the major component of the extracellular matrix (ECM). We found that Delta Np63 is capable of sustaining the production of HA levels in cell culture and in vivo by regulating the expression of the HA synthase HAS3 and two hyaluronidase genes, HYAL-1 and HYAL-3. In addition, Delta Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, Delta Np63 sustains the epithelial growth factor receptor (EGF-R) activation and the expression of ABCC1 multidrug transporter gene, thus contributing to tumor cell proliferation and chemoresistance. Importantly, p63 expression is positively correlated with CD44, HAS3, and ABCC1 expression in squamous cell carcinoma datasets and p63-HA pathway is a negative prognostic factor of HNSCC patient survival. Altogether, our data shed light on a Delta Np63-dependent pathway functionally important to the regulation of HNSCC progression.