An Axis between the Long Non-Coding RNA and NQOs Enhances Metastatic Ability in Oral Squamous Cell Carcinoma.

Long non-coding RNAs (lncRNAs) play critical roles in human cancers. HOXA11 anti-sense RNA () is an lncRNA belonging to the homeobox (HOX) gene cluster that promotes liver metastasis in human colon cancer. However, its role and mechanism of action in human oral squamous cell carcinoma (OSCC) are unclear. In this study, we investigated expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that expression in human OSCC cases correlates with lymph node metastasis, nicotinamide adenine dinucleotide (NAD)(P)H: quinone oxidoreductase 1 () upregulation, and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 () downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that promotes expression by sponging microRNA-494. In contrast, recruits zeste homolog 2 (EZH2) to the promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by results in the consumption of flavin adenine dinucleotide (FAD), which reduces FAD-requiring glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity and suppresses glycolysis. However, our analyses show that lactic acid fermentation levels are preserved by glutaminolysis due to increased malic enzyme-1 expression, promoting enhanced proliferation, invasion, survival, and drug resistance. In contrast, suppression of expression reduces the consumption of NRH via NQO2 enzymatic activity and increases NAD levels, which promotes enhanced stemness and metastatic potential. In mouse tumor models, knockdown of HOXA11-AS markedly suppressed tumor growth and lung metastasis. From these findings, targeting may strongly suppress high-grade OSCC by regulating both and .