权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of EZH2 in Medulloblastoma Tumorigenesis

EZH2 在髓母细胞瘤肿瘤发生中的作用

基本信息

批准号：
8752934
负责人：
Rajeev Vibhakar
金额：
$ 33.91万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8752934
关键词：
Animals Apoptosis Automobile Driving Biological Biology Catalytic Domain Cell Proliferation Cells Cerebellum Child Childhood Brain Neoplasm Chromatin Chromatin Remodeling Factor Clinical Clinical Trials Core Protein Data Disease Enzymes Epigenetic Process Erinaceidae Event Gene Expression Gene Silencing Gene Targeting Genes Genetic Genomics Histone H3 Histones In Vitro Knock-in Mouse Laboratories Lesion Lysine Malignant Neoplasms Malignant neoplasm of brain Mediating Mission Molecular Morbidity - disease rate Mus Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neuronal Differentiation Other Genetics Outcome Patients Pharmacodynamics Play Public Health Radiosurgery Research Role SHH gene Stem cells Subgroup Testing Therapeutic Toxic effect Translations Treatment Efficacy Tumor Biology Tumor Stem Cells Validation Work Xenograft Model adverse outcome chemotherapy clinically relevant effective therapy genome-wide analysis histone modification human EZH2 protein improved in vivo in vivo Model inhibitor/antagonist insight medulloblastoma mouse Cre recombinase mouse model nerve stem cell new therapeutic target novel novel therapeutics overexpression pre-clinical programs promoter public health relevance self-renewal small molecule therapeutic target tumor tumor growth tumor initiation tumorigenesis

项目摘要

ABSTRACT Medulloblastoma is the most common malignant brain tumor that afflicts children. Despite therapy with surgery, radiation and chemotherapy, outcomes of these highly toxic treatments are sub-optimal with significant long-term morbidity. Medulloblastoma consists of 4 distinct molecular subgroups (Wnt, Sonic Hedgehog, Group 3 and Group 4). Among these, Group 4 medulloblastoma is the most common subgroup but its underlying biology is the least characterized. We have recently demonstrated a critical role for Enhancer of Zeste Homolog 2 (EZH2) in Group 4 medulloblastoma. EZH2 is the catalytic core protein of the PRC2 chromatin-remodeling complex, which catalyzes the trimethylation of histone3 lysine27 (H3K27me3) and mediates epigenetic silencing of genes involved in cell fate decisions, differentiation and cancer. We demonstrated that EZH2 is overexpressed in Group 4 medulloblastoma patients, regulates the proliferation and self-renewal capacity of medulloblastoma cells and that the H3K27me3 mark is enriched in Group 4 medulloblastoma patients associated with adverse outcomes. However, the mechanisms underlying EZH2 mediated control of medulloblastoma tumorigenesis are poorly understood. Our preliminary data demonstrates that EZH2 suppresses expression of key regulators of neuronal differentiation and promotes transformation of neural stem cells, raising the intriguing possibility that aberrant EZH2 expression enforces a neuronal differentiation block and maintains pluripotent state in neural and tumor stem cells. The exact gene expression programs regulated by EZH2 in medulloblastoma are unknown and the impact of abnormal EZH2 expression in the cerebellum is undetermined. We hypothesize that EZH2 mediates medulloblastoma tumorigenesis by inhibiting differentiation of cerebellar stem cells and maintaining a pluripotent state. Our objective is to examine the biological impact of EZH2 on medulloblastoma tumorigenesis and test potential novel therapeutic molecules targeting EZH2. To pursue our hypothesis we will first investigate the proposition that EZH2 suppresses gene expression of neuronal differentiation programs in medulloblastoma by altering chromatin occupancy of the H3K27me3 histone core at key promoters. Next we will pursue concept that aberrantly increased EZH2 expression in Group 4 specific cerebellar stem cells will inhibit differentiation and induce tumor formation in the murine cerebellum using a novel mouse model of medulloblastoma. Finally we will test three clinically relevant inhibitors in vivo using patient derived xenograft models of medulloblastoma. Successful completion of the proposed work will determine the role of EZH2 in medulloblastoma and establish the potential of therapeutically targeting this enzyme in clinically relevant in vivo models.

摘要髓母细胞瘤是困扰儿童的最常见的恶性脑肿瘤。尽管治疗与手术、放疗和化疗，这些高毒性治疗的结果是次优的，严重的长期发病率。髓母细胞瘤由4个不同的分子亚群组成（Wnt，Sonic Hedgehog，第3组和第4组）。其中第4组髓母细胞瘤最为常见亚组，但其潜在的生物学是最少的特点。我们最近展示了一个关键的 Zeste增强子同源物2（EZH2）在第4组髓母细胞瘤中的作用。EZH2是催化核心 PRC2染色质重塑复合物的蛋白质，催化组蛋白3的三甲基化赖氨酸27（H3K27me3）并介导参与细胞命运决定的基因的表观遗传沉默，分化和癌症。我们证明EZH2在第4组髓母细胞瘤中过表达，患者，调节髓母细胞瘤细胞的增殖和自我更新能力， H3K27me3标记在与不良结局相关的第4组髓母细胞瘤患者中富集。然而，EZH2介导的髓母细胞瘤肿瘤发生控制的潜在机制是不太了解。我们的初步数据表明，EZH2抑制关键基因的表达，调节神经元分化，促进神经干细胞的转化，提高有趣的可能性是，异常EZH2表达会导致神经元分化阻滞，维持神经和肿瘤干细胞的多能状态。精确的基因表达程序髓母细胞瘤中EZH 2的调节尚不清楚，EZH 2表达异常对髓母细胞瘤的影响小脑尚未确定。我们假设EZH2通过以下途径介导髓母细胞瘤的发生：抑制小脑干细胞的分化并维持多能状态。我们的目标是研究EZH2对髓母细胞瘤肿瘤发生的生物学影响，并测试潜在的新的靶向EZH2的治疗分子。为了继续我们的假设，我们将首先研究以下命题： EZH2通过以下方式抑制髓母细胞瘤中神经元分化程序的基因表达改变H3K27me3组蛋白核心在关键启动子处的染色质占有率。接下来我们将继续第4组特异性小脑干细胞中EZH2表达的异常增加将抑制分化和诱导肿瘤形成的小鼠小脑中使用一种新的小鼠模型，髓母细胞瘤最后，我们将使用患者来源的药物在体内测试三种临床相关的抑制剂。髓母细胞瘤的异种移植模型。成功完成所提出的工作将确定EZH2在髓母细胞瘤中的作用，在临床相关的体内模型中建立治疗靶向这种酶的潜力。