A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect.
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.
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Paula
P
Lopez-Serra
Proteomics Unit, Spanish National Biotechnology Centre (CNB), CSIC, 28049 Madrid, Spain.
Miguel
M
Marcilla
Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Alberto
A
Villanueva
Proteobotics SL, Spanish National Biotechnology Centre (CNB), Darwin 3, 28049 Madrid, Spain.
Antonio
A
Ramos-Fernandez
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Anna
A
Palau
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Lucía
L
Leal
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Jessica E
JE
Wahi
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Fernando
F
Setien-Baranda
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Karolina
K
Szczesna
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Catia
C
Moutinho
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Anna
A
Martinez-Cardus
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Holger
H
Heyn
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Juan
J
Sandoval
Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Sara
S
Puertas
Bellvitge Biomedical Research Institute (IDIBELL), Department of Pathology, Bellvitge University Hospital, L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
August
A
Vidal
Bellvitge Biomedical Research Institute (IDIBELL), Department of Pathology, Bellvitge University Hospital, L'Hospitalet, Barcelona, 08908 Catalonia, Spain.
Xavier
X
Sanjuan
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.
Eva
E
Martinez-Balibrea
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.
Francesc
F
Viñals
Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Spain.
Jose C
JC
Perales
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus N, DK-8200 Aarhus, Denmark.
Jesper B
JB
Bramsem
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus N, DK-8200 Aarhus, Denmark.
Torben F
TF
Ørntoft
Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus N, DK-8200 Aarhus, Denmark.
Claus L
CL
Andersen
Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, 08035 Catalonia, Spain.
Josep
J
Tabernero
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Ultan
U
McDermott
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20891-4874, USA.
Matthew B
MB
Boxer
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.
Matthew G
MG
Vander Heiden
Proteomics Unit, Spanish National Biotechnology Centre (CNB), CSIC, 28049 Madrid, Spain.
Juan Pablo
JP
Albar
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.
Manel
M
Esteller
D000818:Animals; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D059748:Proteolysis
C509686:DERL3 protein, human; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; C495677:SLC2A1 protein, human; D010100:Oxygen