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

被引：80

作者：

Lopez-Serra, Paula ^{[1
]}

Marcilla, Miguel ^{[2
]}

Villanueva, Alberto ^{[3
]}

Ramos-Fernandez, Antonio ^{[4
]}

Palau, Anna ^{[1
]}

Leal, Lucia ^{[1
]}

Wahi, Jessica E. ^{[1
]}

Setien-Baranda, Fernando ^{[1
]}

Szczesna, Karolina ^{[1
]}

Moutinho, Catia ^{[1
]}

Martinez-Cardus, Anna ^{[1
]}

Heyn, Holger ^{[1
]}

Sandoval, Juan ^{[1
]}

Puertas, Sara ^{[3
]}

Vidal, August ^{[5
]}

Sanjuan, Xavier ^{[5
]}

Martinez-Balibrea, Eva ^{[6
]}

Vinals, Francesc ^{[3
,7
]}

Perales, Jose C. ^{[7
]}

Bramsem, Jesper B. ^{[8
]}

Orntoft, Torben F. ^{[8
]}

Andersen, Claus L. ^{[8
]}

Tabernero, Josep ^{[9
]}

McDermott, Ultan ^{[10
]}

Boxer, Matthew B. ^{[11
]}

Vander Heiden, Matthew G. ^{[12
,13
]}

Pablo Albar, Juan ^{[2
]}

Esteller, Manel ^{[1
,7
,14
]}

机构：

[1] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Catalonia, Spain

[2] CSIC, Spanish Natl Biotechnol Ctr CNB, Prote Unit, E-28049 Madrid, Spain

[3] Bellvitge Biomed Res Inst IDIBELL, Catalan Inst Oncol ICO, Translat Res Lab, Barcelona 08908, Catalonia, Spain

[4] Proteobotics SL, Spanish Natl Biotechnol Ctr CNB, Madrid 28049, Spain

[5] Bellvitge Univ Hosp, Dept Pathol, Bellvitge Biomed Res Inst IDIBELL, Barcelona 08908, Catalonia, Spain

[6] Hosp Badalona Germans Trias & Pujol, Inst Invest Ciencies Salut Germans Trias & Pujol, Catalan Inst Oncol ICO, Med Oncol Serv, Barcelona 08916, Catalonia, Spain

[7] Univ Barcelona, Sch Med, Dept Physiol Sci 2, E-08036 Barcelona, Spain

[8] Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark

[9] Vall dHebron Univ Hosp, Dept Med Oncol, Barcelona 08035, Catalonia, Spain

[10] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England

[11] NIH, Natl Ctr Adv Translat Sci, Rockville, MD 20891 USA

[12] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[13] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[14] Inst Catalana Recerca & Estudis Avancats, Barcelona 08010, Catalonia, Spain

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

PYRUVATE-KINASE M2; UNFOLDED PROTEIN RESPONSE; CELL-METABOLISM; CANCER; METHYLATION; LACTATE; PKM2; IDENTIFICATION; TRANSLOCATION; DISLOCATION;

D O I：

10.1038/ncomms4608

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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