3 years ago

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

Susanne I. Wells, Miki Watanabe, Marie C. Matrka, Lindsey E. Romick-Rosendale, Paul F. Lambert, Andrew N. Lane, Ranjithmenon Muraleedharan

by Marie C. Matrka, Miki Watanabe, Ranjithmenon Muraleedharan, Paul F. Lambert, Andrew N. Lane, Lindsey E. Romick-Rosendale, Susanne I. Wells

The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.pone.0177952

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