title: FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression.
abstract: OBJECTIVE
  The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism.
  
  
  METHODS
  The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens.
  
  
  RESULTS
  We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 (PGK-1) and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both the mRNA and protein level and elevated LDH activity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1-LDHA signaling increased the pancreatic cancer cell growth and metastasis.
  
  
  CONCLUSIONS
  Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in patients with pancreatic cancer via transcriptional regulation of LDHA expression.
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurg
authors.forename: Jiujie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TexasAuthors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Xie
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shaojiang
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Authors' Affiliations: Shanghai Key Laboratory of Pancreatic Diseases Research; Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital; Department of General Surgery, Shanghai Jiaotong University Affiliated Ruijin Hospital; Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai; Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Pathology Department of Affiliated Hospital, Hainan Medical College, Haikou, People's Republic of China; Departments of Gastroenterology, Hepatology, and Nutrition; and Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas kepxie@mdanderson.org.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5