title: 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.
authors.affiliation: Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.|Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yun
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Pharmacy, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: Mingling
authors.initials: M
authors.lastname: Wen
authors.affiliation: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.affiliation: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wen
authors.affiliation: State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D065150:Cellular Reprogramming / Q000502:physiology; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; C000609700:HK2 protein, human; D006593:Hexokinase; D005947:Glucose
keywords: FOXM1; GLUT1; HK2; epithelial ovarian cancer; glucose metabolism