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

Nat Commun 2014 Apr 3;5:3608. Epub 2014 Apr 3.

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.

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.

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http://dx.doi.org/10.1038/ncomms4608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988805PMC
April 2014
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