Abstract
Warburg effect is a hallmark of cancer cells, wherein glycolysis is preferred over oxidative phosphorylation even in aerobic conditions. Reprogramming of glycometabolism is especially crucial for malignancy in glioma. RNA-binding proteins and long noncoding RNAs are important for aerobic glycolysis during malignant transformation. Thus, we determined the expression and function of RNA-binding protein Lin28A, long noncoding RNA SNHG14, and transcription factor IRF6 in human glioma cells to elucidate the mechanism(s) underlying their role in glycolysis. Quantitative real-time polymerase chain reaction and western blotting showed that Lin28A and SNHG14 were overexpressed and IRF6 was downregulated in glioma. Depleting Lin28A from cells decreased the stability and expression of SNHG14. Furthermore, depleting SNHG14 reduced IRF6 mRNA degradation by targeting its 3′ untranslated region and inhibiting STAU1-mediated degradation, thereby increasing the expression of IRF6. PKM2 is an important enzyme in aerobic glycolysis, and GLUT1 is the primary transporter that facilitates glucose uptake. IRF6 inhibited the transcription of PKM2 and GLUT1, thereby impairing glycolysis and cell proliferation and inducing apoptosis in glioma. Notably, depleting Lin28A and SNHG14 and overexpressing IRF6 reduced the growth of xenograft tumors in vivo and prolonged the survival of nude mice. Taken together, our data revealed that the Lin28A/SNHG14/IRF6 axis is crucial for reprogramming glucose metabolism and stimulating tumorigenesis in glioma cells. Thus, targeting this axis might help in the development of a novel therapeutic strategy for glioma metabolism.
Highlights
Glioma is the most common and lethal malignant primary brain tumor that is highly aggressive with a very poor prognosis
Since Pyruvate kinase isozyme type M2 (PKM2) and GLUT1 are well-known regulators of glycolysis in tumors, we further investigate whether PKM2 and GLUT1 were involved in Lin28A-mediated reprogramming of glucose metabolism in glioma
Interferon regulatory factor 6 (IRF6) bound the promoters of PKM2 and GLUT1, and inhibited their transcription expression, thereby impairing aerobic glycolysis and tumorigenesis in glioma
Summary
Glioma is the most common and lethal malignant primary brain tumor that is highly aggressive with a very poor prognosis. In contrast to normal cells, tumor cells rely on glycolysis to metabolize glucose even in normoxic conditions; this is called the Warburg effect[3]. Glycolysis is inefficient in supplying ATP, the acidic microenvironment and intermediate metabolites generated by glycolysis are essential for malignant proliferation in glioma[4,5,6]. Lin28A is important for the differentiation and proliferation of cancer as well as regulating cell metabolism[7]. Lin28A is overexpressed in liver cancer[8] and colorectal cancer[9]. Lin[28] is overexpressed in glioblastoma and stimulates cell proliferation[11]. The effect of Lin28A on glycolysis in glioma is unknown
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