Taurine up‐regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma

Abstract

Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3 0 untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKb2).The TUG1/miR-455-3p/AMPKb2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Conclusion: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKb2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (HEPATOLOGY 2018;67:188-203) H epatocellular carcinoma (HCC) is one of the most common malignant liver tumors worldwide. Long-term prognosis for HCC remains extremely poor, with metastasis being the major underlying cause of mortality.(1) Advances in our understanding of the mechanisms underlying metastasis in HCC and strategies to enhance the efficacy of current treatment options are essential to improve prognosis.The metabolic properties of cancer cells are distinct from those of normal cells.(2) Cancer cells exhibit unique metabolic phenotypes, such as enhanced uptake of glucose and conversion of pyruvate to lactate. This phenomenon, termed the Warburg effect, confers Abbreviations: 2-DG, 2-deoxyglucose; AMPKb2, adenosine monophosphate-activated protein kinase subunit beta 2; ChIP, chromatin immunoprecipitation; EED, embryonic ectoderm development; EZH2, enhancer of zeste homolog

Long non-coding RNA TUG1 promotes cell progression in hepatocellular carcinoma via regulating miR-216b-5p/DLX2 axis

“…To sum up, these date manifested a tumorigenic gene role of TUG1 in HCC. A previous study reported that knockdown of TUG1 markedly retarded cell growth, metastasis and glycolysis in HCC [28]. This implied that TUG1 might regulate other behaviors of HCC cells, which requires further study.…”

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…The liver microenvironment is naturally more conducive to cells that display a high glycolytic profile and are adapted for a low-oxygen state. This is illustrated by the abundance of studies demonstrating that primary hepatocellular carcinomas preferentially engage in glycolytic metabolism to proliferate in the liver (Jiao et al, 2017; Lin et al, 2017; Song et al, 2015). It is therefore tempting to speculate that to colonize the liver, metastasizing cancer cells from other organs must be able to overcome this hypoxic barrier in order to adapt to the hepatic environment.…”

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

“…These extensive connections between cancer metabolism and aggressive cancer features suggest that targeting metabolic pathways may be a promising effective method for treating cancer patients. Recent research demonstrated that cancer metabolism reprogramming can be regulated by both coding and noncoding genes via targeting glycolysis‐related transporters, enzymes and signalling pathways (Cairns et al , 2011; Lin et al , 2018; Yang et al , 2014). A previous study and our recent publication demonstrated that a key glycolytic transporter, glucose transporter 1 (GLUT1), is specifically overexpressed in HCC and promotes HCC cell glycolysis and progression (Amann et al , 2009; Shang et al , 2017).…”