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

Abstract

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.

Optical Redox Imaging Detects the Effects of DEK Oncogene Knockdown on the Redox State of MDA-MB-231 Breast Cancer Cells

“…In this study we demonstrated that the ORI-based redox indices can detect the changes directly induced by knock down of DEK gene expressions. DEK gene overexpression has been reported to reprogram metabolism in squamous cell carcinoma resulting in enhanced glycolysis and NAD + [29]. Considering that FAD/(NADH+FAD) is a surrogate indicator of intracellular NAD + /(NAD + +NADH) redox ratio [7], our data indicate that DEK knockdown changes intracellular NAD-coupled redox state.…”

“…It remains unclear which component is responsible for the observed signal change. DEK overexpression has been reported to enhance glycolysis and mitochondrial respiration spared capacity, and knockdown of DEK decreased the transcription of metabolic enzymes regulating glycolysis and NAD metabolism [29]. It would be interesting to further investigate whether FAD signal decrease in our study might be associated with the suppression of the transcription of some of the redox enzymes.…”

Dek overexpression in murine epithelia increases overt esophageal squamous cell carcinoma incidence

“…For instance, Dek knockout mice are viable and resistant to chemically induced papillomas and HPV E7 driven HNSCC. In vitro , DEK overexpression in primary keratinocytes extends life span, stimulates transforming activities of classical oncogenes, and de-regulates cellular metabolism [ 16 , 17 , 78 ]. These data are in line with, but do not prove, oncogenic activities that promote cancer development at the organismal level.…”

Cancer Cell Metabolism: Implications for X-ray and Particle Radiation Therapy

“…Global benefits to the tumor that are produced by a switch to aerobic glycolysis remain elusive, but studies have demonstrated a variety of likely scenarios, including evasion of the immune system, stimulation of neo-vascularization, and selection for drug-resistant cancer cell clones. Interestingly, the activation of oncogenes such as Ras [11], Akt [12], Myc [13], and Dek [14] is in and of itself sufficient for increased cellular glucose uptake and glycolysis. Given that oncogene activation is an early event in tumor development, the switch to a glycolytic metabolism and associated benefits to the tumor appear to be equally early events in the disease process.…”