New activities of the human DEK oncogene

抽象的。 这一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，以及 因此与许多人类癌症类型有关，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 对于早期诊断和新的药物靶点仍然势在必行。DEK是一种高度保守的蛋白质，与核结合 酸化并调节各种核过程，包括转录。我们已经证明dek是一种癌基因， 据报道，DEK过表达可延长原代人类角质形成细胞的寿命，诱导其增殖 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，以及 促进HPV+和HPV-HNSCC和乳腺癌细胞的增殖和侵袭。我们的数据还表明 DEK的过表达增加了β-连环蛋白的活性，而这个DEK-β-连环蛋白轴是必需的，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量和生物合成的能力。 对癌细胞持续生长的需求。最近，我们报道了dek的过度表达增加了转录。 糖酵解、乳酸发酵和胆固醇合成以及代谢物积累中的关键酶 是糖酵解的最终产物。然而，目前尚不清楚DEK驱动的代谢是否需要β-连环蛋白。 重新编程，我们不知道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是唯一针对线粒体的，并且 DEK过表达可刺激细胞氧化磷酸化能力。在提出的3个目标中，我们测试2 假设。首先，DEK的过度表达通过2个离散的DEK池促进HNSCC的致癌表型 它们导致代谢紊乱，一个核(Aim1)和一个线粒体(AIM2)。第二，目标是 无论是β-连环蛋白，还是代谢特征的脆弱节点，都是预防人非小细胞肺癌的有效策略 表型。与稳定同位素分解代谢组学技术的专家合作，我们将产生 由DEK过表达控制的新陈代谢网络的原子分辨图谱，然后将使用该图谱 识别和验证用于药物靶向和诊断生物标记物的新的代谢流脆弱性(Aim3)。 综上所述，拟议的实验是迈向创新预防和 通过代谢干预改善HNSCC预后的治疗策略。

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.