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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. !

项目总结/文摘