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 Bertram Bramsen; Torben F Ørntoft; Claus Lindbjerg Andersen; Josep Tabernero; Ultan McDermott; Matthew B Boxer; Matthew G Vander Heiden; Juan Pablo Albar; Manel Esteller

doi:10.1038/ncomms4608

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 Bertram BramsenTorben F Ørntoft, Claus Lindbjerg Andersen, Josep Tabernero, Ultan McDermott, Matthew B Boxer, Matthew G Vander Heiden, Juan Pablo Albar, Manel Esteller

Department of Clinical Medicine - Department of Molecular Medicine (MOMA)

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

89 Citations (Scopus)

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.

Original language	English
Article number	3608
Journal	Nature Communications
Volume	5
Number of pages	12
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms4608
Publication status	Published - 3 Apr 2014

Keywords

Animals
CpG Islands
DNA Methylation
Gene Expression Regulation, Neoplastic
Glucose Transporter Type 1
Glycolysis
Humans
Membrane Proteins
Mice, Nude
Neoplasms
Oxygen
Promoter Regions, Genetic
Proteolysis

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Lopez-Serra, P., Marcilla, M., Villanueva, A., Ramos-Fernandez, A., Palau, A., Leal, L., Wahi, J. E., Setien-Baranda, F., Szczesna, K., Moutinho, C., Martinez-Cardus, A., Heyn, H., Sandoval, J., Puertas, S., Vidal, A., Sanjuan, X., Martinez-Balibrea, E., Viñals, F., Perales, J. C., ... Esteller, M. (2014). A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nature Communications, 5, Article 3608. https://doi.org/10.1038/ncomms4608

@article{d0c59547cdb7464d90ae9550dee6cdcc,

title = "A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect",

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.",

keywords = "Animals, CpG Islands, DNA Methylation, Gene Expression Regulation, Neoplastic, Glucose Transporter Type 1, Glycolysis, Humans, Membrane Proteins, Mice, Nude, Neoplasms, Oxygen, Promoter Regions, Genetic, Proteolysis",

author = "Paula Lopez-Serra and Miguel Marcilla and Alberto Villanueva and Antonio Ramos-Fernandez and Anna Palau and Luc{\'i}a Leal and Wahi, {Jessica E} and Fernando Setien-Baranda and Karolina Szczesna and Catia Moutinho and Anna Martinez-Cardus and Holger Heyn and Juan Sandoval and Sara Puertas and August Vidal and Xavier Sanjuan and Eva Martinez-Balibrea and Francesc Vi{\~n}als and Perales, {Jose C} and Bramsen, {Jesper Bertram} and {\O}rntoft, {Torben F} and Andersen, {Claus Lindbjerg} and Josep Tabernero and Ultan McDermott and Boxer, {Matthew B} and {Vander Heiden}, {Matthew G} and Albar, {Juan Pablo} and Manel Esteller",

year = "2014",

month = apr,

day = "3",

doi = "10.1038/ncomms4608",

language = "English",

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journal = "Nature Communications",

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Lopez-Serra, P, Marcilla, M, Villanueva, A, Ramos-Fernandez, A, Palau, A, Leal, L, Wahi, JE, Setien-Baranda, F, Szczesna, K, Moutinho, C, Martinez-Cardus, A, Heyn, H, Sandoval, J, Puertas, S, Vidal, A, Sanjuan, X, Martinez-Balibrea, E, Viñals, F, Perales, JC, Bramsen, JB , Ørntoft, TF , Andersen, CL, Tabernero, J, McDermott, U, Boxer, MB, Vander Heiden, MG, Albar, JP & Esteller, M 2014, 'A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect', Nature Communications, vol. 5, 3608. https://doi.org/10.1038/ncomms4608

TY - JOUR

T1 - A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect

AU - Lopez-Serra, Paula

AU - Marcilla, Miguel

AU - Villanueva, Alberto

AU - Ramos-Fernandez, Antonio

AU - Palau, Anna

AU - Leal, Lucía

AU - Wahi, Jessica E

AU - Setien-Baranda, Fernando

AU - Szczesna, Karolina

AU - Moutinho, Catia

AU - Martinez-Cardus, Anna

AU - Heyn, Holger

AU - Sandoval, Juan

AU - Puertas, Sara

AU - Vidal, August

AU - Sanjuan, Xavier

AU - Martinez-Balibrea, Eva

AU - Viñals, Francesc

AU - Perales, Jose C

AU - Bramsen, Jesper Bertram

AU - Ørntoft, Torben F

AU - Andersen, Claus Lindbjerg

AU - Tabernero, Josep

AU - McDermott, Ultan

AU - Boxer, Matthew B

AU - Vander Heiden, Matthew G

AU - Albar, Juan Pablo

AU - Esteller, Manel

PY - 2014/4/3

Y1 - 2014/4/3

N2 - 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.

AB - 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.

KW - Animals

KW - CpG Islands

KW - DNA Methylation

KW - Gene Expression Regulation, Neoplastic

KW - Glucose Transporter Type 1

KW - Glycolysis

KW - Humans

KW - Membrane Proteins

KW - Mice, Nude

KW - Neoplasms

KW - Oxygen

KW - Promoter Regions, Genetic

KW - Proteolysis

U2 - 10.1038/ncomms4608

DO - 10.1038/ncomms4608

M3 - Journal article

C2 - 24699711

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 3608

ER -

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

Abstract

Keywords

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