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Nat Commun. 2014 Apr 3;5:3608. doi: 10.1038/ncomms4608.

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

Author information

1
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
2
Proteomics Unit, Spanish National Biotechnology Centre (CNB), CSIC, 28049 Madrid, Spain.
3
Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
4
Proteobotics SL, Spanish National Biotechnology Centre (CNB), Darwin 3, 28049 Madrid, Spain.
5
Bellvitge Biomedical Research Institute (IDIBELL), Department of Pathology, Bellvitge University Hospital, L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
6
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, Badalona, Barcelona, 08916 Catalonia, Spain.
7
1] Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain [2] Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Spain.
8
Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Spain.
9
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus N, DK-8200 Aarhus, Denmark.
10
Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, 08035 Catalonia, Spain.
11
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
12
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20891-4874, USA.
13
1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
14
1] Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain [2] Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Spain [3] Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, 08010 Catalonia, Spain.

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.

PMID:
24699711
PMCID:
PMC3988805
DOI:
10.1038/ncomms4608
[Indexed for MEDLINE]
Free PMC Article
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