New activities of the human DEK oncogene

摘要。 这项建议建立在我们过去对人类DEK基因的研究基础上，该基因被扩增和过度表达， 因此涉及许多人类癌症类型，包括头颈部鳞状细胞癌（HNSCC）。 HNSCC是世界上第六大最常见的恶性肿瘤-结果令人沮丧。生物标志物的鉴定 早期诊断和新的药物靶点仍然是当务之急。DEK是一种高度保守的蛋白质， 酸和调节不同的核过程，包括转录。我们已经证明DEK是一种致癌基因， 通过报道DEK过表达延长了原代人角质形成细胞的寿命，诱导增生， 在表皮的3D模型中，与经典癌基因合作刺激角质形成细胞转化， 促进HPV+和HPV- HNSCC和乳腺癌细胞增殖和侵袭。我们的数据还表明， DEK过表达增加β-catenin活性，这种DEK-β-catenin轴是必需的，也是足够的， 一些癌症表型。 肿瘤转化的一个主要障碍是细胞满足高生物能和生物合成的能力。 需要持续的癌细胞生长。最近，我们报道了DEK过表达增加转录， 糖酵解、乳酸发酵和胆固醇合成中的关键酶，以及代谢产物的积累 糖酵解的最终产物。然而，目前尚不清楚β-连环蛋白是否是DEK驱动的代谢所必需的。 我们不了解糖酵解和胆固醇合成在DEK驱动的癌症中的作用 表型最后，在初步研究中，我们发现DEK是唯一靶向线粒体的， DEK过表达刺激细胞氧化磷酸化能力。在提出的3个目标中，我们测试了2个 假设首先，DEK过表达通过2个离散的DEK库促进HNSCC致癌表型， 驱动代谢失调的基因，一个是核基因（Aim 1），一个是线粒体基因（Aim 2）。第二，瞄准 β-catenin或代谢特征的脆弱节点是预防HNSCC的有效策略 表型通过与稳定同位素解析代谢组学技术专家的合作，我们将产生 一个由DEK过表达控制的代谢网络的原子分辨图，然后将使用这个图来 识别和验证药物靶向和诊断生物标志物的新型代谢通量漏洞（Aim 3）。 总的来说，拟议的实验是朝着创新性预防迈出的重要的第一步， 通过代谢干预改善HNSCC结局的治疗策略。

ABSTRACT. This proposal builds on our past studies of the human DEK gene, which is amplified and overexpressed, and thus implicated in many human cancer types including head and neck squamous cell carcinoma (HNSCC). HNSCC is the sixth most common malignancy worldwide - with dismal outcomes. Identification of biomarkers for early diagnosis and new drug targets remains imperative. DEK is a highly conserved protein that binds nucleic acids and regulates diverse nuclear processes, including transcription. We have shown that DEK is an oncogene, by reporting that DEK overexpression extends the life span of primary human keratinocytes, induces hyperplasia in 3D models of epidermis, cooperates with classical oncogenes to stimulate keratinocyte transformation, and promotes HPV+ and HPV– HNSCC and breast cancer cell proliferation and invasion. Our data also demonstrated that DEK overexpression increases β-catenin activity, and this DEK-β-catenin axis is required and sufficient for some cancer phenotypes. A major hurdle in neoplastic transformation is the ability of cells to meet high bioenergetic and biosynthetic needs for sustained cancer cell growth. Recently, we reported that DEK overexpression increases transcription of key enzymes in glycolysis, lactate fermentation and cholesterol synthesis, and accumulation of metabolites that are glycolytic end products. However, it is not known whether β-catenin is required for DEK-driven metabolic reprogramming, and we do not understand the role of glycolysis and cholesterol synthesis in DEK-driven cancer phenotypes. Finally, in preliminary studies, we discovered that DEK is uniquely targeted to mitochondria, and DEK overexpression stimulated cellular oxidative phosphorylation capacity. In the proposed 3 aims, we test 2 hypotheses. First, that DEK overexpression promotes HNSCC oncogenic phenotypes by 2 discrete pools of DEK which drive metabolic deregulation, one nuclear (Aim1) and one mitochondrial (Aim2). Second, that targeting either β-catenin, or vulnerable nodes of the metabolic signature is an effective strategy to prevent HNSCC phenotypes. In partnership with an expert in stable isotope resolved metabolomics technologies, we will generate an atom-resolved map of metabolic networks controlled by DEK overexpression, and will then use this map to identify and validate novel metabolic flux vulnerabilities for drug targeting and diagnostic biomarkers (Aim3). Taken together, the proposed experiments represent a significant first step towards innovative prevention and treatment strategies to improve the outcomes of HNSCC via metabolic interventions.