FOXM1 promotes reprogramming of glucose metabolism in epithelial ovarian cancer cells via activation of GLUT1 and HK2 transcription

Abstract

Cancer cells exhibit the reprogrammed metabolism mainly via aerobic glycolysis, a phenomenon known historically as the Warburg effect; however, the underlying mechanisms remain largely unknown. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in aerobic glycolysis of human epithelial ovarian cancer (EOC) and its molecular mechanisms. Our data showed that aberrant expression of FOXM1 significantly contributed to the reprogramming of glucose metabolism in EOC cells. Aerobic glycolysis and cell proliferation were down-regulated in EOC cells when FOXM1 gene expression was suppressed by RNA interference. Moreover, knockdown of FOXM1 in EOC cells significantly reduced glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression. FOXM1 bound directly to the GLUT1 and HK2 promoter regions and regulated the promoter activities and the expression of the genes at the transcriptional level. This reveals a novel mechanism by which glucose metabolism is regulated by FOXM1. Importantly, we further demonstrated that the expression levels of FOXM1, GLUT1 and HK2 were significantly increased in human EOC tissues relative to normal ovarian tissues, and that FOXM1 expression was positively correlated with GLUT1 and HK2 expression. Taken together, our results show that FOXM1 promotes reprogramming of glucose metabolism in EOC cells via activation of GLUT1 and HK2 transcription, suggesting that FOXM1 may be an important target in aerobic glycolysis pathway for developing novel anticancer agents.

PPARα Promotes Cancer Cell Glut1 Transcription Repression

“…In addition, to fuel cancer cell growth and malignancy, cancer cells could alter some oncogentic gene (MYC, IDH1, kRas) abnormal expressions, subsequently, increase Glut1 expression and accelerate glucose uptake and process of anabolic glucose metabolism [Flier et al, 1987;Dang et al, 2009;Ying et al, 2012;Boroughs and DeBerardinis, 2015]. Furthermore, FOXM1 (Forkhead box protein M1) could promote reprogramming of glucose metabolism via inducing Glut1 expression [Wang et al, 2016]. The deprivation of glucose triggers the K-Ras mutation and Glut1 expression that could enhance glucose uptake and cell survival in low-glucose conditions [Yun et al, 2009].…”

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

“…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.…”

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

“…Our findings suggest that promotion of glycolysis triggers tumor metastasis in HCC cell lines. HK2, a rate‐determining enzyme in aerobic glycolysis, is overexpressed in many cancer types, including glioblastoma multiforme, lung cancer, and ovarian cancer . Further, the regulation of HK2 is mediated by lncRNA urothelial cancer‐associated 1, miRNA, or epigenetic alterations .…”