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

Paula Lopez-Serra, Miguel Marcilla, Alberto Villanueva, Antonio Ramos-Fernandez, Anna Palau, Lucía Leal, Jessica E. Wahi, Fernando Setien-Baranda, Karolina Szczesna, Catia Moutinho, Anna Martinez-Cardus, Holger Heyn, Juan Sandoval, Sara Puertas, August Vidal, Xavier Sanjuan, Eva Martinez-Balibrea, Francesc Viñals, Jose C. Perales, Jesper B. Bramsem, Torben F. Ørntoft, Claus L. Andersen, Josep Tabernero, Ultan McDermott, Matthew B. Boxer, Matthew G. Vander Heiden, Juan Pablo Albar and Manel Esteller ()
Additional contact information
Paula Lopez-Serra: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Miguel Marcilla: Proteomics Unit, Spanish National Biotechnology Centre (CNB), CSIC
Alberto Villanueva: Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Antonio Ramos-Fernandez: Proteobotics SL, Spanish National Biotechnology Centre (CNB)
Anna Palau: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Lucía Leal: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Jessica E. Wahi: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Fernando Setien-Baranda: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Karolina Szczesna: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Catia Moutinho: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Anna Martinez-Cardus: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Holger Heyn: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Juan Sandoval: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Sara Puertas: Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
August Vidal: Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital, L'Hospitalet
Xavier Sanjuan: Bellvitge Biomedical Research Institute (IDIBELL), Bellvitge University Hospital, L'Hospitalet
Eva Martinez-Balibrea: Medical Oncology Service, Catalan Institute of Oncology (ICO), l'Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias I Pujol
Francesc Viñals: Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet
Jose C. Perales: School of Medicine, University of Barcelona
Jesper B. Bramsem: Aarhus University Hospital
Torben F. Ørntoft: Aarhus University Hospital
Claus L. Andersen: Aarhus University Hospital
Josep Tabernero: Vall d’Hebron University Hospital
Ultan McDermott: Cancer Genome Project, Wellcome Trust Sanger Institute
Matthew B. Boxer: National Center for Advancing Translational Sciences, National Institutes of Health
Matthew G. Vander Heiden: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Juan Pablo Albar: Proteomics Unit, Spanish National Biotechnology Centre (CNB), CSIC
Manel Esteller: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Cancer cells possess aberrant proteomes that can arise by the disruption of genes involved in physiological protein degradation. Here we demonstrate the presence of promoter CpG island hypermethylation-linked inactivation of DERL3 (Derlin-3), a key gene in the endoplasmic reticulum-associated protein degradation pathway, in human tumours. The restoration of in vitro and in vivo DERL3 activity highlights the tumour suppressor features of the gene. Using the stable isotopic labelling of amino acids in cell culture workflow for differential proteome analysis, we identify SLC2A1 (glucose transporter 1, GLUT1) as a downstream target of DERL3. Most importantly, SLC2A1 overexpression mediated by DERL3 epigenetic loss contributes to the Warburg effect in the studied cells and pinpoints a subset of human tumours with greater vulnerability to drugs targeting glycolysis.

Date: 2014
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DOI: 10.1038/ncomms4608

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