Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis.
Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis.
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DOI：
10.1371/journal.pone.0177952
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wells SI
中科院分区：
文献类型：
--
作者：
Matrka MC;Watanabe M;Muraleedharan R;Lambert PF;Lane AN;Romick-Rosendale LE;Wells SI
DEK癌基因在许多人类恶性肿瘤中过度表达，包括在早期肿瘤阶段。我们对鳞状细胞癌的体外和体内模型的报道表明，DEK对细胞和肿瘤的存活以及增殖有功能上的贡献。然而，潜在的分子机制仍然知之甚少。根据最近的RNA测序实验，DEK的表达对于参与合成代谢途径的几种代谢酶的转录是必需的。这确定了一个可能的机制，其中DEK可能驱动细胞代谢，使细胞增殖。海马功能代谢分析显示，dek过表达的角质形成细胞和鳞状细胞癌细胞的基线和最大细胞外酸化率（糖酵解的读数）增加。DEK过表达也增加了最大耗氧量，因此增加了氧化磷酸化（OxPhos）的潜力。为了检测参与糖酵解和为OxPhos提供底物的三羧酸循环（TCA）的小代谢物，我们进行了基于核磁共振的代谢组学研究。我们发现，高水平的DEK显著地重编程了细胞代谢，改变了氨基酸、TCA循环中间体和糖酵解终产物乳酸、丙氨酸和NAD+的丰度。综上所述，这些数据支持了一种观点，即人类DEK癌基因的过度表达重新编程了角质细胞的代谢，以满足能量和大分子的需求，从而实现和维持癌细胞的生长。
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.