Long non-coding RNAs (lncRNAs) play critical roles in human
cancers. HOXA11
anti-sense RNA (HOXA11-AS) 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 HOXA11-AS expression and function in human OSCC tissues and cell lines, as well as a mouse model of OSCC. Our analyses showed that HOXA11-AS expression in human OSCC cases correlates with
lymph node metastasis,
nicotinamide adenine dinucleotide (
NAD)(P)H:
quinone oxidoreductase 1 (NQO1) upregulation, and
dihydronicotinamide riboside (NRH):
quinone oxidoreductase 2 (
NQO2) downregulation. Using the human OSCC cell lines HSC3 and HSC4, we demonstrate that HOXA11-AS promotes NQO1 expression by sponging microRNA-494. In contrast, HOXA11-AS recruits zeste homolog 2 (EZH2) to the
NQO2 promoter to suppress its expression via the trimethylation of H3K27. The upregulation of NQO1 enzymatic activity by HOXA11-AS 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
NQO2 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 HOXA11-AS may strongly suppress high-grade OSCC by regulating both NQO1 and
NQO2.