The role of JMJD6 in MYC-mediated neuroblastoma

JMJD6在MYC介导的神经母细胞瘤中的作用

基本信息

批准号：
9538645
负责人：
Jun Yang
金额：
$ 8.98万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-03 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9538645
关键词：
Affective Apoptosis Arginine Binding Biological Bromodomain Cell Cycle Cell Line Cell Survival Cessation of life ChIP-seq Child Chromosomes Combined Modality Therapy Coupled DNA Methylation Data Development Disease Disease model Doxycycline Drug resistance Enhancers Epigenetic Process Frequencies Gene Expression Gene Targeting Genes Genetic Transcription Genomics Growth Histone H4 Histones Human In Vitro Lung Lysine MYC gene MYCN gene Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mediating Methylation Modeling Modification Molecular Abnormality Neoplasm Metastasis Neural Crest Cell Neuroblastoma Oncogenic Outcome Ovarian Pathogenesis Pathway Analysis Patients Pharmacologic Substance Play Proteins Role Signal Pathway Solid Neoplasm Somatic Mutation Subfamily lentivirinae Survival Rate Sympathetic Nervous System Testing Transgenic Mice Untranslated RNA Ursidae Family Work Zebrafish angiogenesis antitumor effect c-myc Genes cancer therapy cancer type childhood cancer mortality chromatin modification disorder risk high risk histone demethylase histone modification improved in vivo in vivo Model infancy inhibitor/antagonist insight knock-down loss of function melanoma mouse model neural growth neuroblastoma cell new therapeutic target outcome forecast overexpression programs small hairpin RNA small molecule stemness therapeutic target transcription factor transcriptome sequencing tumor tumor growth tumor progression tumorigenesis tumorigenic

项目摘要

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. !

项目概要/摘要神经母细胞瘤是一种实体瘤，由神经嵴细胞异常生长引起发展交感神经系统。它是婴儿期最常见的癌症类型并导致高达 15% 的儿童癌症死亡率。尽管成果显着改善患有低风险疾病的儿童的存活率高于患有高风险神经母细胞瘤的儿童的存活率尽管强化多模式治疗，该比例仍低于 40%。因此，确定新的治疗方法神经母细胞瘤的目标势在必行。 MYC 癌基因（C-MYC、MYCN 和 MYCL1）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 放大是最重要的生物学特征。转基因小鼠和斑马鱼模型证明 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 过度表达，表明神经母细胞瘤是一种 MYC 驱动的癌症。不过，直接靶向非激素转录因子（例如 C-MYC/MYCN）在技术上具有挑战性。最近的基因组测序数据显示，神经母细胞瘤的体细胞发生率非常低突变，表明表观遗传学失调可能与发病机制有关。我们最近的研究表明 MYCN 劫持组蛋白赖氨酸去甲基化酶 KDM4B 以促进其功能。我们的随后的研究表明组蛋白精氨酸去甲基化酶JMJD6的表达为与 MYCN 状态相关并与不良结果相关，表明 JMJD6 发挥着重要作用在神经母细胞瘤中发挥重要作用。其他人之前的研究表明，JMJD6 在物理上与 BRD4 相互作用，调节 C-MYC/MYCN 表达。然而，JMJD6是否重要 C-MYC/MYCN 表达和/或功能未知。这里我们建议表征该函数 JMJD6 在 MYC 介导的神经母细胞瘤中的作用。我们将通过体外和体外实验来确定 JMJD6 的作用。该疾病的体内模型（目标 1），从而验证 JMJD6 作为治疗靶点。我们也会通过使用 RNA-seq、ChIP-seq 和通路分析来定义 JMJD6 在神经母细胞瘤中的功能鉴定 JMJD6 靶基因、基因组结合、与其组蛋白底物修饰的相关性，以及 MYC 基因组占用（目标 2）。拟议的工作将探索新的治疗靶点神经母细胞瘤并建立开发小分子药物靶向的基本原理 JMJD6在癌症治疗中的应用。此外，它将提供有关 MYC-表观遗传修饰因子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携带 JMJD6 扩增的癌症（例如黑色素瘤、肺癌和卵巢癌）。！