FOXM1 regulates glycolysis in hepatocellular carcinoma by transactivating glucose transporter 1 expression

Abstract

Abstract. The Forkhead box M1 (FOXM1) transcription factor plays crucial roles in the initiation and progression of various malignancies, including hepatocellular carcinoma (HCC). However, the mechanism by which FOXM1 regulates cancer metabolism remains unclear. In the present study, overexpression and RNA interference (RNAi) approaches were used to investigate the role of FOXM1 in the regulation of glycolysis in vitro. Luciferase reporter assays were used to explore the transcriptional regulation of the glucose transporter 1 (GLUT1) promoter by FOXM1. Then, immunohistochemical staining was used to examine the expression of FOXM1 and GLUT1 in 100 paired HCC and adjacent non-cancerous liver tissues. Chi-square test and logistic regression analysis were performed to evaluate the association between FOXM1 and GLUT1 expression with clinicopathological characteristics. Our data showed that FOXM1 promoted glycolysis in the HCC cells. FOXM1 knockdown significantly reduced the expression of GLUT1 among key glycolysis-related molecules in the different HCC cell lines. Glucose uptake and lactate production assay showed that FOXM1 positively regulated glycolysis based on GLUT1 expression. Moreover, FOXM1 overexpression increased and knockdown decreased GLUT1 expression. Luciferase reporter assays showed that the -206 to -199 bp region of the GLUT1 promoter is important for FOXM1 to enhance GLUT1 promoter activity. The results of the IHC analysis showed that the protein expression of FOXM1 and GLUT1 was closely related to the tumor histological grade and TNM stage. In addition, GLUT1 expression was also related to microvascular invasion. In conclusion, overexpression of FOXM1 and GLUT1 may play critical roles in HCC. FOXM1 promotes HCC glycolysis by transactivating GLUT1 expression. IntroductionHepatocellular carcinoma (HCC) is one of the most prevalent neoplasms and the second leading cause of cancer-related mortality worldwide (1). Despite the application of surgical resection, ablation, embolization and other therapeutic methods, the overall prognosis of patients with HCC remains poor and the incidence of HCC is increasing annually (2,3). Therefore, the underlying mechanisms that promote the pathogenesis of this deadly disease must be further investigated.Metabolic reprogramming has long been linked to cancer. One of the classical theories of metabolic abnormality in tumors is the Warburg effect, which describes increased glycolysis even under normal oxygen conditions (4). The shift of the metabolic pathway from oxidative phosphorylation to glycolysis is more rapid to meet the demands necessary for the process of tumor progression. However, it is inefficient to generate ATP by consuming units of glucose under glycolysis conditions (5). Therefore, transformed cells need to uptake more glucose than normal cells. The glucose transporter 1 (GLUT1) isoform is a key rate-limiting protein in the transport of glucose and is overexpressed in HCC (6). However, the mechanism underlying increased glycolysis by targeting GLUT1 in HCC...

MicroRNA-761 promotes the sensitivity of colorectal cancer cells to 5-Fluorouracil through targeting FOXM1

“…Increasing studies showed that FOXM1 played critical roles in cell cycle, DNA replication, invasion, migration, angiogenesis and drug resistance [ 41 – 44 ]. FOXM1 expression was found to be upregulated in several tumors such as gastric cancer, hepatocellular carcinoma, lung caner, glioma and also colorectal cancer [ 42 , 45 – 48 ]. For example, Zheng et al [ 49 ].…”

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

“…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). We further revealed that GLUT1 is transactivated by the transcription factor Forkhead box M1 (FOXM1) in different cancer types (Shang et al , 2017; Wang et al , 2016).…”

“…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). We further revealed that GLUT1 is transactivated by the transcription factor Forkhead box M1 (FOXM1) in different cancer types (Shang et al , 2017; Wang et al , 2016). However, knowledge of how noncoding genes regulate GLUT1 expression is lacking.…”

FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer

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