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A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect

Paula Lopez-Serra1, Miguel Marcilla2, Alberto Villanueva3

  • 1Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.

Nature Communications
|April 5, 2014
PubMed

Insights

Cancer cells can inactivate the DERL3 gene through epigenetic changes, leading to increased glucose transporter GLUT1. This promotes the Warburg effect and makes tumors more susceptible to glycolysis-targeting drugs.

Area of Science:

  • Molecular biology
  • Cancer research
  • Epigenetics

Background:

  • Aberrant proteomes in cancer cells often result from disrupted protein degradation pathways.
  • The endoplasmic reticulum-associated protein degradation (ERAD) pathway is crucial for maintaining proteostasis.

Purpose of the Study:

  • To investigate the role of DERL3 (Derlin-3) gene inactivation in human tumors.
  • To identify downstream targets of DERL3 and their contribution to cancer phenotypes.

Main Methods:

  • Analysis of promoter CpG island hypermethylation to detect DERL3 inactivation.
  • Proteome analysis using stable isotopic labeling of amino acids in cell culture (SILAC).
  • In vitro and in vivo experiments to restore DERL3 activity.

Main Results:

  • Promoter CpG island hypermethylation inactivates DERL3 in human tumors.
  • DERL3 inactivation leads to overexpression of SLC2A1 (glucose transporter 1, GLUT1).
  • Restoring DERL3 activity demonstrated its tumor suppressor function.

Conclusions:

  • Epigenetic silencing of DERL3 contributes to the Warburg effect via GLUT1 upregulation.
  • This epigenetic alteration identifies a subset of tumors vulnerable to glycolysis inhibitors.
  • DERL3 acts as a tumor suppressor by regulating proteostasis and glucose metabolism.

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