Long noncoding RNA SLC2A1‐AS1 regulates aerobic glycolysis and progression in hepatocellular carcinoma via inhibiting the STAT3/FOXM1/GLUT1 pathway

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal malignant diseases worldwide. Despite advances in the diagnosis and treatment of HCC, its overall prognosis remains poor. Recent studies have shown that long noncoding RNAs (lncRNAs) play crucial roles in various pathophysiological processes, including liver cancer. In the current study, we report that lncRNA SLC2A1‐AS1 is frequently downregulated in HCC samples, as shown by quantitative real‐time polymerase chain reaction analysis. SLC2A1‐AS1 deletion is significantly associated with recurrence‐free survival in HCC. By performing glucose uptake, lactate production and ATP detection assays, we found that SLC2A1‐AS1‐mediated glucose transporter 1 (GLUT1) downregulation significantly suppressed glycolysis of HCC. In vitro Cell Counting Kit‐8, colony formation, transwell assays as well as in vivo tumorigenesis and metastasis assays showed that SLC2A1‐AS1 overexpression significantly suppressed proliferation and metastasis in HCC through the transcriptional inhibition of GLUT1. Results from fluorescence in situ hybridization, ChIP and luciferase reporter assays demonstrated that SLC2A1‐AS1 exerts its regulatory role on GLUT1 by competitively binding to transketolase and signal transducer and activator of transcription 3 (STAT3) and inhibits the transactivation of Forkhead box M1 (FOXM1) via STAT3, thus resulting in inactivation of the FOXM1/GLUT1 axis in HCC cells. Our findings will be helpful for understanding the function and mechanism of lncRNA in HCC. These data also highlight the crucial role of SLC2A1‐AS1 in HCC aerobic glycolysis and progression and pave the way for further research regarding the potential of SLC2A1‐AS1 as a valuable predictive biomarker for HCC recurrence.

Keywords

• FOXM1
• GLUT1
• glycolysis
• hepatocellular carcinoma
• long noncoding RNA
• STAT3