title: Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance.
abstract: OBJECTIVE
  Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance.
  
  
  METHODS
  In vitro and in vivo functional assays were performed to study the effects of Id1-E2F1-IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes.
  
  
  RESULTS
  Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types.
  
  
  CONCLUSIONS
  Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment.
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China. Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China.
authors.forename: Wen Wen
authors.initials: WW
authors.lastname: Xu
authors.affiliation: Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Xin Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
authors.forename: Yan Ru
authors.initials: YR
authors.lastname: Qin
authors.affiliation: Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Department of Surgery The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Simon
authors.initials: S
authors.lastname: Law
authors.affiliation: Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Department of Surgery The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Nikki Pui Yue
authors.initials: NP
authors.lastname: Lee
authors.affiliation: Department of Surgery The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Kin Tak
authors.initials: KT
authors.lastname: Chan
authors.affiliation: Department of Surgery The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Pui Ying
authors.initials: PY
authors.lastname: Tam
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China.
authors.forename: Yuk Yin
authors.initials: YY
authors.lastname: Li
authors.affiliation: The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China. Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore.
authors.forename: Hiu Fung
authors.initials: HF
authors.lastname: Yuen
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
authors.forename: Qing Yu
authors.initials: QY
authors.lastname: He
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), China. Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. lmcheung@hku.hk.
authors.forename: Annie L M
authors.initials: AL
authors.lastname: Cheung
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013940:Thymidylate Synthase / Q000096:biosynthesis
chemical_list: D064199:Cdc20 Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497453:ID1 protein, human; C035170:IGF2 protein, human; D051798:Inhibitor of Differentiation Protein 1; C577488:CDC20 protein, human; D007335:Insulin-Like Growth Factor II; D013940:Thymidylate Synthase; D005472:Fluorouracil