UCLA

The initiation and development of head and neck squamous cell carcinoma (HNSCC) is a complex process, but the underlying mechanisms remain unclear. In this study, we found acyl-CoA thioesterase 7 (ACOT7), a novel metabolic enzyme, was significantly upregulated in HNSCC tumor tissues versus the adjacent normal tissues and in HNSCC cell lines versus normal human oral keratinocytes (NHOK). HNSCC patients with high ACOT7 expression suffered from unfavorable disease-free and overall survival rates compared to those with low ACOT7 expression, which was also observed in many other types of human cancers. Silencing ACOT7 significantly inhibited the proliferation, migration, invasion, and tumor-sphere formation of HNSCC cells, whereas overexpressing ACOT7 significantly promoted the proliferation, migration, invasion, and tumor sphere formation of HNSCC cells. Meanwhile, arachidonic acid, the product of ACOT7 enzymatic reaction, also had a promoting effect on the proliferation, colony formation, and migration of HNSCC cells. Furthermore, we demonstrated that MYC transcriptionally upregulated the expression of ACOT7 in HNSCC cells, whereas MYC inhibitor significantly suppressed ACOT7 expression in a dose-dependent manner. Lastly, RNA-sequencing, followed by functional pathway analysis, revealed that p53 signaling was one of the downstream target pathways of ACOT7 in HNSCC cells. Using Western blot analysis and immunofluorescence, we demonstrated that ACOT7 downregulation, through arachidonic acid, significantly prohibited AKT but not phospho-AKT, which in turn inhibited the expression of phospho-MDM2 but not total MDM2 and led to the upregulation of p53 in HNSCC cells. In conclusion, our studies demonstrated the functional significance of ACOT7 and the related regulatory pathway of MYC-ACOT7-AKT-MDM2-p53 axis in promoting HNSCC progression. Our findings revealed novel metabolic mechanisms in HNSCC and target genes with therapeutic interventions.