Histone methyltransferase EZH2 in liver pathophysiology and carcinogenesis

组蛋白甲基转移酶 EZH2 在肝脏病理生理学和癌发生中的作用

• 批准号: 8201357
• 负责人: HONG LU
• 金额: $ 7.98万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-02 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201357
• 关键词: Abbreviations; Adult; Antineoplastic Agents; Apoptosis; Apoptotic; Applications Grants; Area; Carcinogenesis Inhibition; Catalytic Domain; Cell Aging; Cell Proliferation; Cells; Chemotherapy-Oncologic Procedure; Complex; DNA Methylation; Data; Disease; Doctor of Philosophy; Drug Delivery Systems; E2F1 gene; Embryo; Embryonic Development; Ensure; Epigenetic Process; Essential Genes; Event; Functional disorder; Gene Silencing; Genes; Goals; Growth; Hepatocarcinogenesis; Hepatocyte; Histone H3; Human; In Vitro; Incidence; Injury; Knock-out; Knockout Mice; Knowledge; Laboratories; Liver; Liver Regeneration; Liver diseases; Lysine; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; MicroRNAs; Modeling; Molecular; Mus; Natural regeneration; Nude Mice; Oncogene Activation; Oncogenes; Partial Hepatectomy; Play; Polycomb; Prevention; Preventive; Primary carcinoma of the liver cells; Research; Risk; Role; Safety; Solid; Structure of beta Cell of islet; Testing; Therapeutic; Training; Trans-Activators; Tumor Suppressor Proteins; Tumorigenicity; United States; Work; anticancer research; c-myc Genes; c-myc Proto-Oncogenes; cancer cell; carcinogenesis; chemotherapy; effective therapy; histone methyltransferase; human EZH2 protein; improved; in vivo; inhibitor/antagonist; injury and repair; mouse model; neonate; novel; novel strategies; outcome forecast; overexpression; prevent; senescence; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The long term goal is to understand the molecular mechanism of hepatocarcinogenesis so that novel strategies for the effective prevention and treatment of liver cancer can be developed. Epigenetic abnormity is a major hallmark in hepatocellular carcinogenesis. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays a key role in embryonic development via catalyzing trimethylation of histone H3 at lysine-27 and facilitating DNA methylation. EZH2 is overexpressed in human liver cancer, and knockdown of EZH2 causes apoptosis of liver cancer cells and tumor regression in nude mice. However, little is known about the in vivo importance of EZH2 in liver pathophysiology and carcinogenesis, largely due to the embryonic lethality of EZH2-null mice. Additionally, activation of the oncogene c-Myc causes liver cancer in mice, and c-Myc overexpression is associated with malignant transformation of hepatocytes in humans; however, the underlying mechanism of c-Myc-induced hepatocarcinogenesis remains unclear. The objective of this proposal is to elucidate the pathophysiological importance of EZH2 in liver utilizing novel models of mice with liver-specific knockout (LKO) of EZH2 and/or overexpression of c-Myc. We found that EZH2-LKO mice appeared normal, suggesting that loss of EZH2 in liver is well-tolerated. EZH2 is essential for the regeneration of pancreatic beta cells. We found that EZH2 was markedly induced during liver regeneration, suggesting its importance for the regeneration of liver. The central hypothesis is that EZH2 is important for liver regeneration and is required for c-Myc-induced hepatocarcinogenesis through inhibiting c-Myc-induced cell senescence/apoptosis and promoting c-Myc-induced cell proliferation. Knockout of EZH2 will cause a significant delay of liver regeneration and blockage of c-Myc-induced hepatocarcinogenesis. This central hypothesis will be tested in two specific aims. Aim 1 will determine the importance of EZH2 in liver regeneration using models of 2/3 partial hepatectomy in EZH2-LKO mice. The working hypothesis is that EZH2-LKO mice will have considerable delay in liver regeneration but will eventually regenerate the liver due to compensatory mechanism(s). Aim 2 will determine the importance of EZH2 in c-Myc-induced liver carcinogenesis using mice with liver-specific knockout of EZH2 but overexpression of c-Myc. The working hypothesis is that EZH2 deficiency will prevent c-Myc-induced liver cancer via inhibiting cell proliferation but enhancing cell apoptosis/senescence. Results from this study will provide crucial novel knowledge about the importance of EZH2 in liver regeneration and liver carcinogenesis, which may ultimately help to identify EZH2 as a novel target for the prevention and treatment of liver cancer, a deadly disease with increasing incidence in the USA. Moreover, understanding the role of EZH2 in liver regeneration will help to determine how EZH2 inhibitors may influence liver injury-repair and the safety of chemotherapy when EZH2 inhibitors are combined with other anticancer drugs to treat diverse malignancies. PUBLIC HEALTH RELEVANCE: The United States has increasing incidence of liver cancer, a deadly disease that lacks effective treatment. The proposed studies are of importance in the under-investigated area of epigenetic control of liver regeneration and liver carcinogenesis by a novel histone methyltransferase EZH2. Thus, the findings are expected to enhance our understanding of liver diseases and liver cancer, and this knowledge can be used to develop new drug target to prevent and treat liver cancer.

描述（申请人提供）：长期目标是了解肝癌发生的分子机制，以便开发有效预防和治疗肝癌的新策略。表观遗传异常是肝细胞癌发生的一个主要标志。 zeste 同源物 2 (EZH2) 的组蛋白甲基转移酶增强子通过催化组蛋白 H3 在赖氨酸 27 处的三甲基化并促进 DNA 甲基化，在胚胎发育中发挥关键作用。 EZH2在人肝癌中过度表达，敲除EZH2可导致肝癌细胞凋亡和裸鼠肿瘤消退。然而，人们对 EZH2 在肝脏病理生理学和癌发生中的体内重要性知之甚少，这主要是由于 EZH2 缺失小鼠的胚胎致死性。此外，癌基因c-Myc的激活会导致小鼠肝癌，而c-Myc过度表达与人类肝细胞的恶性转化有关；然而，c-Myc 诱导肝癌发生的潜在机制仍不清楚。本提案的目的是利用肝脏特异性敲除 (LKO) EZH2 和/或 c-Myc 过度表达的新型小鼠模型，阐明 EZH2 在肝脏中的病理生理学重要性。我们发现 EZH2-LKO 小鼠表现正常，表明肝脏中 EZH2 的缺失具有良好的耐受性。 EZH2 对于胰腺 β 细胞的再生至关重要。我们发现EZH2在肝再生过程中被显着诱导，表明其对肝再生的重要性。中心假设是EZH2对肝再生很重要，并且是c-Myc诱导的肝癌发生所必需的，通过抑制c-Myc诱导的细胞衰老/凋亡和促进c-Myc诱导的细胞增殖。 EZH2 的敲除将导致肝再生显着延迟并阻断 c-Myc 诱导的肝癌发生。这一中心假设将在两个具体目标中得到检验。目标 1 将使用 EZH2-LKO 小鼠 2/3 部分肝切除模型确定 EZH2 在肝再生中的重要性。目前的假设是，EZH2-LKO 小鼠的肝脏再生会出现相当大的延迟，但由于补偿机制，最终会再生肝脏。目标 2 将使用肝脏特异性敲除 EZH2 但过度表达 c-Myc 的小鼠来确定 EZH2 在 c-Myc 诱导的肝癌发生中的重要性。目前的假设是，EZH2 缺陷将通过抑制细胞增殖但增强细胞凋亡/衰老来预防 c-Myc 诱导的肝癌。这项研究的结果将提供关于 EZH2 在肝再生和肝癌发生中的重要性的重要新知识，这可能最终有助于将 EZH2 确定为预防和治疗肝癌的新靶标，肝癌是一种在美国发病率不断上升的致命疾病。此外，了解EZH2在肝再生中的作用将有助于确定当EZH2抑制剂与其他抗癌药物联合治疗多种恶性肿瘤时，EZH2抑制剂如何影响肝损伤修复以及化疗的安全性。 公共卫生相关性：美国肝癌的发病率不断上升，这是一种缺乏有效治疗的致命疾病。所提出的研究对于新型组蛋白甲基转移酶 EZH2 对肝再生和肝癌发生的表观遗传控制这一尚待研究的领域具有重要意义。因此，这些发现有望增强我们对肝病和肝癌的认识，并且这些知识可用于开发预防和治疗肝癌的新药物靶点。