The role of JMJD6 in MYC-mediated neuroblastoma

项目总结/摘要 神经母细胞瘤是一种实体瘤，它是由神经嵴细胞的异常生长引起的。 发展中的交感神经系统它是婴儿期最常见的癌症类型， 高达15%的儿童癌症死亡率。虽然结果有了显著改善， 对于低风险疾病的儿童， 尽管进行了密集的多模式治疗，但仍低于40%。因此，鉴定新的治疗剂 神经母细胞瘤的靶点是当务之急MYC癌基因（C-MYC、MYCN和MYCL 1）属于 人类癌症中最常见的遗传异常，包括神经母细胞瘤，其中MYCN 扩增是最重要的生物学特征。转基因小鼠和斑马鱼模型具有 证明MYCN驱动神经母细胞瘤。在没有MYCN扩增的患者中，我们发现， C-MYC过表达，表明神经母细胞瘤是MYC驱动的癌症。然而，直接 靶向非激素转录因子如C-MYC/MYCN在技术上具有挑战性。最近 基因组测序数据显示，神经母细胞瘤具有非常低的体细胞癌发生率， 突变，表明失调的表观遗传学可能参与发病机制。我们最近 研究表明，MYCN劫持组蛋白赖氨酸脱甲基酶KDM 4 B以促进其功能。我们 随后的研究表明，组蛋白精氨酸脱甲基酶JMJD 6的表达是 与MYCN状态相关，并与不良结局相关，表明JMJD 6起作用， 在神经母细胞瘤中的重要作用。其他人以前的研究表明，JMJD 6在物理上 与调节C-MYC/MYCN表达的BRD 4相互作用。然而，JMJD 6是否重要 C-MYC/MYCN表达和/或功能未知。在这里，我们建议将函数 MYC介导的神经母细胞瘤中JMJD 6的表达。我们将通过体外和体外实验来确定JMJD 6的作用， 在疾病的体内模型（目的1）中，从而验证JMJD 6作为治疗靶标。我们还将 通过使用RNA-seq、ChIP-seq和途径分析来确定JMJD 6在神经母细胞瘤中的功能， 鉴定JMJD 6靶基因、基因组结合、与其组蛋白底物修饰相关性，以及 MYC基因组占有率（Aim 2）。拟议的工作将探索一种新的治疗靶点， 神经母细胞瘤，并建立基本原理，开发小分子药物靶向 JMJD 6在癌症治疗中的应用此外，它将提供有关MYC中表观遗传修饰剂的新见解。 介导的发病机制。我们预计，这项研究的结果也将有利于其他类型的 癌症（例如，黑色素瘤、肺癌和卵巢癌）。 !

Project Summary/Abstract Neuroblastoma is a solid tumor that arises from the aberrant growth of neural crest cells of the developing sympathetic nervous system. It is the most common type of cancer in infancy and causes as much as 15% of childhood cancer mortality. Although remarkable improvements in outcome have been achieved for children with low-risk disease, the survival rate of those with high-risk neuroblastoma remains less than 40% despite intensive multimodal therapies. Thus, identifying novel therapeutic targets for neuroblastoma is imperative. MYC oncogenes (C-MYC, MYCN, and MYCL1) are among the most common genetic abnormalities in human cancer, including neuroblastoma, in which MYCN amplification is the most important biological feature. Transgenic mouse and zebrafish models have demonstrated that MYCN drives neuroblastoma. In patients without MYCN amplification, we found that C-MYC was overexpressed, indicating that neuroblastoma is a MYC-driven cancer. However, directly targeting nonhormonal transcription factors such as C-MYC/MYCN is technically challenging. Recent genomic sequencing data have revealed that neuroblastoma has very low frequencies of somatic mutations, suggesting that deregulated epigenetics might be involved in the pathogenesis. Our recent study indicated that MYCN hijacks the histone lysine demethylase KDM4B to facilitate its function. Our subsequent studies showed that the expression of the histone arginine demethylase JMJD6 is correlated with MYCN status and associated with poor outcome, indicating that JMJD6 plays an important role in neuroblastoma. Previous studies by others have shown that JMJD6 physically interacts with BRD4, which regulates C-MYC/MYCN expression. However, whether JMJD6 is important for C-MYC/MYCN expression and/or function is unknown. Here we propose to characterize the function of JMJD6 in MYC-mediated neuroblastoma. We will determine the role of JMJD6 by using in vitro and in vivo models of the disease (Aim 1), thereby validating JMJD6 as a therapeutic target. We will also define JMJD6 functions in neuroblastoma by using RNA-seq, ChIP-seq, and pathway analysis to identify JMJD6 target genes, genomic binding, correlation with its histone substrate modification, and MYC genomic occupancy (Aim 2). The proposed work will explore a new therapeutic target for neuroblastoma and establish the rationale to develop small molecules to pharmaceutically target JMJD6 in cancer treatment. In addition, it will provide new insight about epigenetic modifiers in MYC- mediated pathogenesis. We anticipate that findings from this study will also benefit other types of cancers (e.g., melanoma, lung, and ovarian cancers) that bear JMJD6 amplification. !