Hypoxia activates various long noncoding RNAs (lncRNAs) to induce the epithelial-mesenchymal transition (EMT) and tumor metastasis. The hypoxia/HIF-1α-regulated lncRNAs that also regulate a specific histone mark and promote EMT and metastasis have not been identified. We performed RNA-sequencing dataset analysis to search for such lncRNAs and lncRNA was the hypoxia-induced lncRNA with the highest hazard ratio. High expression of lncRNA is correlated with a worse survival of head and neck cancer patients. We further showed that lncRNA is induced by hypoxia and directly regulated by HIF-1α in cell lines. Overexpression of lncRNA induces the EMT and increases the migration and invasion and metastatic activity. Knockdown experiments showed that lncRNA plays an essential role in hypoxia-induced EMT. LncRNA specifically regulates the histone 4 lysine 16 acetylation (H4K16Ac) mark that is located on the promoters of two "core" EMT regulators, and , and genes. These results indicate that lncRNA regulates the deposition of H4K16Ac on the promoters of target genes to activate their expression. This report identifies lncRNA as a key player in regulating the histone mark H4K16Ac through which activates downstream target genes to mediate hypoxia-induced EMT.