ΔNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis

Abstract

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 ΔNp63 isoforms is observed in the majority of HNSCCs. Here, we unveiled a ΔNp63-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 ∆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, ∆Np63 directly regulates the expression of CD44, the major HA cell membrane receptor. By controlling this transcriptional program, ∆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 ∆Np63-dependent pathway functionally important to the regulation of HNSCC progression.

ΔNp63 in squamous cell carcinoma: defining the oncogenic routes affecting epigenetic landscape and tumour microenvironment

“…In agreement with this, our group has recently unveiled a novel ΔNp63‐dependent transcriptional oncogenic programme aimed at sustaining the synthesis of one important component of the ECM, hyaluronic acid (HA) (Compagnone et al ., ). In human tumours, HA is pivotal for diverse tumour‐related processes, including cell migration, angiogenesis and metastasis (Chanmee et al ., ; Jiang et al ., ; Toole, ), and several types of cancers including SCC are characterized by relatively high amounts of tumour cell‐associated HA (Koyama et al ., , ; Kultti et al ., ).…”

Metformin and 4SC‐202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

“…ΔNp63 acts primarily in dominant‐negative of P63, while the structure and function of full‐length TA (transactivation) isoform of P63 has similarity to wild‐type P53, the ΔNp63 acts primarily against nearly all family members of P53 . Overexpression of ΔNp63 isoforms is observed in the majority of HNSCCs . In addition, high expression of ΔNp63 contributes to chemoresistance .…”

“…Notably, the combination of metformin and 4SC-202 showed synergistic growth inhibitory effects in OSCC cells. We applied a relatively low dose of metformin (16 mmol/L, IC [30][31][32][33][34][35][36][37][38][39][40] ) and 4SC-202 (0.4 μmol/L, IC [30][31][32][33][34][35][36][37][38][39][40] ) which inhibited tumor growth effectively. For xenograft or 4NQO mouse model, we chose a relatively low dose of metformin (100 mg/kg) and 4SC-202 (80 mg/kg) to lower possible toxicity.…”

“…The results showed that metformin and 4SC-202 suppress the cell viability of OSCC in a time and concentration-dependent manner ( Figure 1A,B). IC [30][31][32][33][34][35][36][37][38][39][40] of HSC3 and HSC6 at 24 hours (metformin, 16 mmol/L; 4SC-202, 0.4 μmol/L) was selected for subsequent experiments in consideration of toxicology. Subsequently, CI index was calculated to determine the combination effects of 4SC-202 and metformin, which revealed that metformin and 4SC-202 synergistically suppress OSCC proliferation as CI < 1 (Figure 1C,D).…”

“…30 ΔNp63 acts as an oncogene which suppresses apoptosis but sustains proliferation, and aberrant expression of ΔNp63 is associated with the poor prognosis of OSCC patients. [30][31][32] Here, we detected the expression of ΔNp63 by western blot and RT-PCR after treating with metformin or/and 4SC-202. The protein level of ΔNp63 was decreased remarkably under 4SC-202 or metformin administration, especially in combined group, but the mRNA level of ΔNp63 remained unperturbed (P > 0.05) ( Figure 4A).…”