UCLA

Metabolic remodeling is now widely regarded as a hallmark of cancer. However, the role of metabolic enzymes in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC) is poorly known. We have identified many novel differentially expressed genes/metabolic enzymes and metabolites between HNSCC and adjacent normal tissues by using transcriptomic and metabolomic analyses. Here, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) was found to be significantly upregulated in HNSCC tumor tissues and cell lines. Patients with higher PLOD3 expression suffered poorer tumor differentiation and worse long term overall survival. This observation was also found in many other types of human cancers. PLOD3 downregulation inhibited cancer cell proliferation, migration and invasion in vitro and tumor growth in vivo, and ectopic expression of PLOD3 potentiated (promoted) cancer cell proliferation, migration and invasion in vitro and tumor growth in vivo. In addition, we explored the potential molecular mechanisms accounting for the pro-carcinogenic role of PLOD3 in HNSCC. MiR-124-3p was demonstrated to be an upstream regulator of PLOD3. Overexpression of miR-124-3p suppressed the proliferation, migration and invasion capacity of HNSCC cells, whereas underexpression of miR-124-3p led to the opposite results. More importantly, PLOD3 overexpression partially rescued the tumor suppressive effect of miR-124-3p, indicating that miR-124-3p was a functional modulator of PLOD3. RNA sequencing (RNA-Seq) was performed to screen the potential downstream effectors of PLOD3. Functional analysis revealed the differentially expressed genes were enriched in actin cytoskeleton regulation and focal adhesion. Furthermore, we observed that PLOD3 downregulation changed the morphology of cancer cells, which failed to attach the surface of the petri dish. Therefore, we hypothesized that focal adhesion kinase (FAK) might be a potential downstream effector of PLOD3. PLOD3 downregulation suppressed the phosphorylation of FAK, PI3K and AKT, and vice versa. Furthermore, FAK inhibition significantly suppressed the tumor-promoting role of PLOD3 in HNSCC. In conclusion, our results have revealed a miR-124-3p-PLOD3-FAK/PI3K/AKT regulatory axis that contributes to the tumorigenesis of HNSCC and PLOD3 might represent a therapeutic target for HNSCC treatment.