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：
9115243
负责人：
Rajeev Vibhakar
金额：
$ 34.02万
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/9115243
关键词：
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 Enhancers Enzymes Epigenetic Process Event Gene Expression Gene Silencing Gene Targeting Genes Genetic Genomics Health Histone H3 Histones Homologous Gene In Vitro 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 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 improved in vivo in vivo Model inhibitor/antagonist insight knockin animal medulloblastoma mouse Cre recombinase mouse model nerve stem cell new therapeutic target novel novel therapeutics overexpression pharmacodynamic biomarker pre-clinical programs promoter self-renewal small molecule therapeutic target tumor tumor growth tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：髓母细胞瘤是困扰儿童的最常见的恶性脑肿瘤。尽管接受了手术，放射线和化学疗法的治疗，但这些剧毒疗法的结果是最佳的，具有显着的长期发病率。髓母细胞瘤由4个不同的分子亚组（Wnt，Sonic Hedgehog，第3组和第4组）组成。其中，第4组髓母细胞瘤是最常见的亚组，但其潜在的生物学的特征最少。最近，我们证明了4组髓母细胞瘤中Zeste同源2（EZH2）增强子的关键作用。 EZH2是PRC2染色质复合物复合物的催化核心蛋白，它催化了组蛋白3赖氨酸27（H3K27ME3）的三甲基化，并介导了涉及细胞命运决策，分化和差异，分化和癌症基因的表观遗传沉默。我们证明了EZH2在第4组髓母细胞瘤患者中过表达，调节了髓母细胞瘤细胞的增殖和自我更新能力，并且H3K27me3 Mark富集于4组髓母细胞瘤患者与不良抗癌相关的髓母细胞瘤患者。然而，EZH2介导的对髓母细胞瘤肿瘤发生的控制的机制知之甚少。我们的初步数据表明，EZH2抑制神经元分化的关键调节剂的表达，并促进神经干细胞的转化，从而提高了异常的EZH2表达可实施神经元分化阻滞并在神经和肿瘤干细胞中维持多能状态的可能性。 EZH2在髓母细胞瘤中调节的确切基因表达程序是未知的，并且不确定EZH2表达异常在小脑中的影响。我们假设EZH2通过抑制小脑干细胞的分化并保持多能状态来介导髓母细胞瘤的肿瘤发生。我们的目标是检查EZH2对髓母细胞瘤肿瘤发生的生物学影响，并测试针对EZH2的潜在新型治疗分子。为了提出我们的假设，我们将首先研究EZH2通过改变关键启动子中H3K27me3组蛋白核心的染色质占用率来抑制髓母细胞瘤中神经元分化程序的基因表达。接下来，我们将追求概念，在第4组小脑干细胞中异常增加EZH2的表达将抑制分化并使用髓母细胞瘤的新型小鼠模型在鼠小脑中诱导肿瘤形成。最后，我们将使用髓母细胞瘤的患者衍生的异种移植模型在体内测试三种临床相关的抑制剂。成功完成拟议的工作将确定EZH2在髓母细胞瘤中的作用，并确定在体内临床相关的治疗靶向该酶的潜力型号。