Evaluating the role of EZH2-interacting protein (EZHIP) in pediatric posterior fossa ependymoma metabolism

评估 EZH2 相互作用蛋白 (EZHIP) 在儿童后颅窝室管膜瘤代谢中的作用

• 批准号: 10368942
• 负责人: Derek Dang
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-02 至 2023-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368942
• 关键词: Advisory Committees; Applications Grants; Automobile Driving; Biology; Brain region; Cancer Biology; Cell Line; Cell Proliferation; Cell Survival; Cells; Childhood; Childhood Ependymoma; Citric Acid Cycle; Clinical; Collaborations; Complex; DNA Methylation; DNA Sequence Alteration; Data; EZH2 gene; Enzymes; Ependymoma; Epigenetic Process; Exhibits; Future; Gene Expression; Genetic; Genetic Transcription; Glycolysis; Goals; Grant; Growth; Hypoxia; Impairment; In Vitro; Interruption; Knowledge; Laboratories; Link; Location; Malignant Childhood Neoplasm; Malignant Neoplasms; Mentors; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Molecular; Mus; Nature; Neuraxis; Outcome; Pathogenesis; Patients; Pharmacology; Posterior Fossa; Production; Prognosis; Proteins; Pyruvate Dehydrogenase Complex; Pyruvate Dehydrogenase E1; RNA Interference; RNA analysis; Recurrence; Resistance; Role; Sampling; Scientist; Solid; Testing; Therapeutic; Training; Training and Education; Treatment Efficacy; Tumorigenicity; Up-Regulation; base; cancer cell; career; cell growth; chemotherapy; effective therapy; epigenetic regulation; experimental study; genomic locus; histone methyltransferase; histone modification; in vivo; insight; knock-down; mRNA Expression; metabolomics; nerve stem cell; neuropathology; novel; novel therapeutics; overexpression; patient derived xenograft model; protein expression; pyruvate dehydrogenase; small hairpin RNA; therapeutic target; therapeutically effective; transcriptome sequencing; tumor; tumor growth; tumor metabolism

ABSTRACT Pediatric ependymomas are the third-most common malignancy of the central nervous system. While they arise in different places of the neuraxis, these tumors are most commonly seen in the posterior fossa region of the brain. Posterior fossa ependymomas have been stratified into two groups (Group A and Group B) based on DNA methylation, transcriptional, and clinical profiling. Of these two groups, Group A (also referred to as PFA) is more invasive and carries a worse prognosis. These tumors are resistant to chemotherapy and arise in sensitive locations that may render them inoperable. PFAs are unusual as more than 80% of these tumors do not bear recurrent genetic mutations. Interestingly, these tumors are defined by global loss of transcriptionally- repressive histone modification H3K27me3 and global gain of transcriptionally-activating histone modification H3K27ac. Alterations in DNA methylation and global H3K27me3 reduction indicate that PFAs are epigenetically driven. EZH2-inhibitory protein (EZHIP) is a novel protein that is expressed highly in PFAs and drives global reduction of H3K27me3 by inhibiting the activity of histone methyltransferase EZH2. It remains unknown how EZHIP expression and H3K27me3 loss drives tumorigenicity in PFA ependymomas. Strikingly, RNA-sequencing analysis of PFAs show upregulation of the pyruvate dehydrogenase complex, a key metabolic complex that links glycolysis and the TCA-cycle. Subsequent metabolomic and RNA analysis show that glycolytic and TCA-cycle metabolism are also enhanced in these tumors. Based on these preliminary data, I hypothesize that EZHIP expression upregulate PFA metabolism by epigenetically activating the pyruvate dehydrogenase complex. To test this hypothesis, I will characterize the epigenetic and metabolic effect of exogenous EZHIP expression in neuronal stem cells and EZHIP deletion in patient-derived PFA cell lines. To define the role of the PDC on tumor pathogenesis, I will target PDC expression via RNA-interference and pharmacological inhibition and determine the effect on PFA growth in vivo and in vitro. These experiments will provide novel mechanistic insights into PFA growth and will provide solid scientific data that may inform future therapeutic strategies.

摘要 小儿室管膜瘤是中枢神经系统第三常见的恶性肿瘤。当他们出现时， 在神经轴的不同部位，这些肿瘤最常见于后颅窝区域， 个脑袋后颅窝室管膜瘤分为两组（A组和B组）， DNA甲基化，转录和临床分析。在这两组中，A组（也称为PFA） 更具侵袭性，预后也更差这些肿瘤对化疗有抵抗力， 敏感的位置，可能使他们无法操作。PFAs是不寻常的，因为超过80%的这些肿瘤都是如此。 不携带复发性基因突变。有趣的是，这些肿瘤的定义是转录- 抑制性组蛋白修饰H3 K27 me 3和转录激活组蛋白修饰的整体获得 H3K27ac。DNA甲基化和H3 K27 me 3整体减少的改变表明PFAs是表观遗传学上的。 有动力。EZH 2抑制蛋白（EZHIP）是一种在PFAs中高表达的新蛋白，它可以驱动细胞内的细胞凋亡。 通过抑制组蛋白甲基转移酶EZH 2的活性减少H3 K27 me 3。目前还不清楚 EZHIP表达和H3 K27 me 3缺失驱动PFA室管膜瘤的致瘤性引人注目的是，RNA测序 PFAs的分析显示丙酮酸脱氢酶复合物的上调，丙酮酸脱氢酶复合物是一种关键的代谢复合物， 糖酵解和TCA循环。随后的代谢组学和RNA分析表明，糖酵解和TCA循环 代谢也在这些肿瘤中增强。基于这些初步数据，我假设EZHIP 表达通过表观遗传激活丙酮酸脱氢酶上调PFA代谢 复杂.为了验证这一假设，我将描述外源性EZHIP的表观遗传和代谢效应， 在神经元干细胞中的EZHIP表达和在患者来源的PFA细胞系中的EZHIP缺失。要定义 PDC在肿瘤发病机制中的作用，我将通过RNA干扰和药物抑制靶向PDC表达 并确定在体内和体外对PFA生长的影响。这些实验将提供新的机制 这些数据将为未来的治疗策略提供可靠的科学数据。