Long non-coding RNA TUG1 regulates multiple glycolytic enzymes in hepatocellular carcinoma cells via sponging microRNA-122-5p

Hepatocellular carcinoma (HCC) remains the third-leading cause of cancer death; however, its therapeutic options are limited. Understanding the molecular mechanisms of HCC could shed light on new therapies. Emerging studies indicate the important role of long-noncoding RNAs (lncRNAs) in the pathogenesis of HCC. The expression of the early discovered lncRNA, taurine-upregulated gene 1 (TUG1), is upregulated in HCC tissues, but its transcriptomic effects in HCC cells remain unexplored. We established TUG1-knockdown and control HCC cells for RNA-seq experiments. KEGG analysis revealed glycolysis as the top-hit pathway upon TUG1 silencing. Accordingly, TUG1-depleted HCC cells showed impairments in glucose uptake, ATP synthesis, and lactate production. Clinical HCC tissue data revealed positive gene expression correlations between TUG1 and several glycolysis genes. To identify a molecular function of TUG1 in glycolysis, we explored the competing endogenous model and used bioinformatic tools to find the five microRNAs (miRNAs) that had the most binding sites for TUG1. Among these miRNAs, miR-122-5p exhibited an inverse correlation in gene expression with most TUG1-regulated glycolysis genes, including PKM, ALDOA, ENO2, and PFKM. Dual luciferase assays demonstrated the direct interaction between TUG1 and miR-122-5p and between miR-122-5p and the 3ʹ untranslated regions of both PKM and ALDOA. We further showed that inhibition of miR-122-5p alleviated the suppression of glycolysis induced by TUG1 depletion. Together, our RNA-seq analysis of TUG1-depleted HCC cells, combined with clinical data, reveals the critical function of TUG1 in promoting glycolysis via sponging miR-122-5p, which is a negative regulator of multiple glycolytic enzymes.