Eukaryotic translation initiation factor 5A2 promotes metabolic reprogramming in hepatocellular carcinoma cells

Abstract

Reprogramming of intracellular metabolism is common in liver cancer cells. Understanding the mechanisms of cell metabolic reprogramming may present a new basis for liver cancer treatment. In our previous study, we reported that a novel oncogene eukaryotic translation initiation factor 5A2 (EIF5A2) promotes tumorigenesis under hypoxic condition. Here, we aim to investigate the role of EIF5A2 in cell metabolic reprogramming during hepatocellular carcinoma (HCC) development. In this study, we reported that the messenger RNA (mRNA) level of EIF5A2 was upregulated in 59 of 105 (56.2%) HCC clinical samples (P = 0.015), and EIF5A2 overexpression was significantly associated with shorter survival time of patients with HCC (P = 0.021). Ectopic expression of EIF5A2 in HCC cell lines significantly promoted cell growth and accelerated glucose utilization and lipogenesis rates. The high rates of glucose uptake and lactate secretion conferred by EIF5A2 revealed an abnormal activity of aerobic glycolysis in HCC cells. Several key enzymes involved in glycolysis including glucose transporter type 1 and 2, hexokinase 2, phosphofructokinase liver type, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2 isoform, phosphoglycerate mutase 1 and lactate dehydrogenase A were upregulated by overexpression of EIF5A2. Moreover, EIF5A2 showed positive correlations with FASN and ACSS2, two key enzymes involved in the fatty acid de novo biosynthetic pathway, at both protein and mRNA levels in HCC. These results indicated that EIF5A2 may regulate fatty acid de novo biosynthesis by increasing the uptake of acetate. In conclusion, our findings demonstrate that EIF5A2 has a critical role in HCC cell metabolic reprogramming and may serve as a prominent novel therapeutic target for liver cancer treatment.

Translating the Game: Ribosomes as Active Players

“…Rate-limiting initiation factors that link 60S ribosome biogenesis to translation as eIF6 hierarchically control lipid synthesis and metabolism, through uORF and G/C rich 5 ′ UTR sequences ( Brina et al, 2015 ). eIF5A2 accelerates lipogenesis in hepatocellular carcinoma ( Cao et al, 2017 ). In general, translation and metabolism are dysregulated in a coordinated fashion ( Leibovitch and Topisirovic, 2018 ), and initiation factors may act upstream of metabolic reprogramming ( Biffo et al, 2018 ).…”

Motile hepatocellular carcinoma cells preferentially secret sugar metabolism regulatory proteins via exosomes

“…In addition, the homeostasis of sugar is partially maintained by oncoproteins and enzymes, such as autocrine motility factor (AMF) that catalyzes the reactions in glycolysis and gluconeogenesis . As such, the metabolic reprograming from mitochondria oxidation to glycolysis has been deemed a necessary step for cancer cells to gain motility that associates with invasiveness and metastasis progression . In this study, we justified remarkably higher level of GAPDH in exosomes from motile HCC cells, which was a key glycolysis enzyme .…”

Eukaryotic translation initiation factor 5A2 is highly expressed in prostate cancer and predicts poor prognosis

“…EIF5A2, Eukaryotic translation initiation factor 5A2; PCa, prostate cancer. enhanced cell metabolic reprogramming (23). Furthermore, ablation of EIF5A2 could induce tumor vasculature remodeling and improve the tumor response to chemotherapy (24).…”