CUE domain-containing protein 2 promotes the Warburg effect and tumorigenesis

EMBO Rep. 2017 May;18(5):809-825. doi: 10.15252/embr.201643617. Epub 2017 Mar 21.


Cancer progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions; however, the underlying mechanisms are still poorly understood. Here, we report that CUEDC2 (CUE domain-containing protein 2) plays a vital role in facilitating aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we show that CUEDC2 upregulates the two key glycolytic proteins GLUT3 and LDHA via interacting with the glucocorticoid receptor (GR) or 14-3-3ζ, respectively. We further demonstrate that enhanced aerobic glycolysis is essential for the role of CUEDC2 to drive cancer progression. Moreover, using tissue microarray analysis, we show a correlation between the aberrant expression of CUEDC2, and GLUT3 and LDHA in clinical HCC samples, further demonstrating a link between CUEDC2 and the Warburg effect during cancer development. Taken together, our findings reveal a previously unappreciated function of CUEDC2 in cancer cell metabolism and tumorigenesis, illustrating how close oncogenic lesions are intertwined with metabolic alterations promoting cancer progression.

Keywords: LDHA; CUEDC2; GLUT3; Warburg effect; tumorigenesis.

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Adaptor Proteins, Signal Transducing
  • Carcinogenesis*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Glucose Transporter Type 3 / genetics
  • Glucose Transporter Type 3 / metabolism
  • Glycolysis*
  • HeLa Cells
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Lactate Dehydrogenase 5
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Receptors, Glucocorticoid / metabolism
  • Tissue Array Analysis
  • Transcriptional Activation
  • Up-Regulation


  • 14-3-3 Proteins
  • Adaptor Proteins, Signal Transducing
  • CUEDC2 protein, human
  • Carrier Proteins
  • Glucose Transporter Type 3
  • Isoenzymes
  • Membrane Proteins
  • Receptors, Glucocorticoid
  • SLC2A3 protein, human
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5