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Histone methyltransferase G9a in liver pathophysiology and carcinogenesis

组蛋白甲基转移酶 G9a 在肝脏病理生理学和癌发生中的作用

基本信息

批准号：
8100463
负责人：
HONG LU
金额：
$ 7.74万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8100463
关键词：
Abbreviations Adult Apoptosis Applications Grants Area Automobile Driving C-Terminal Binding Protein 1 C-terminal binding protein CCAAT displacement protein Cell Proliferation Chromosomes, Human, Pair 10 Cirrhosis DNA Methylation DNA Methyltransferase DNA Modification Methylases Data Disease Doctor of Philosophy Down-Regulation Drug Delivery Systems Embryo Embryonic Development Ensure Epigenetic Process Fatty Liver Functional disorder G9a histone methyltransferase Gene Silencing Goals Growth Growth Factor Hepatocarcinogenesis Hepatocyte Histone H3 Homologous Gene Human Hypoxia Incidence Knock-out Knockout Mice Knowledge Laboratories Liver Liver Cirrhosis Liver Regeneration Liver diseases Lysine Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of prostate Mediating Minor Modeling Molecular Mus Neoplasm Metastasis PTEN gene Partial Hepatectomy Pharmaceutical Preparations Phosphoric Monoester Hydrolases Play Prevention Preventive Process Public Health Research Signal Pathway Solid Steatohepatitis Telomere Length Maintenance Telomere Shortening Testing Therapeutic Training Transcription Repressor/Corepressor Transgenes Tumor Suppressor Genes Tumor Suppressor Proteins United States Work cancer cell carcinogenesis effective therapy gene repression hepatoma cell histone methyltransferase human TERT protein in vivo inhibitor/antagonist lipid biosynthesis liver function mouse model novel novel strategies prevent promoter protein expression regenerative small heterodimer partner protein tensin tumor progression

项目摘要

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. Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) in hepatocytes causes progressive steatohepatitis and liver cancer; the epigenetic silencing of PTEN and other tumor suppressors is associated with dimethylation of histone H3 at lysine-9 (H3K9me2), a key suppressive mark for gene silencing. The histone methyltransferase G9a plays a key role in embryonic development through catalyzing H3K9me2 and facilitating DNA methylation by DNA methyltransferases. G9a mediates gene repression by a group of transcriptional repressors/corepressors important in steatohepatitis and carcinogenesis. Knockdown of G9a causes dramatic down-regulation of telomere reverse transcriptase and apoptosis of cancer cells. G9a is induced in human liver cancer; however, little is known about the in vivo importance of G9a in liver pathophysiology and carcinogenesis, largely due to the embryonic lethality of G9a-null mice. The objective of this proposal is to elucidate the pathophysiological importance of G9a in liver utilizing novel models of mice with hepatocyte-specific knockout (HKO) of G9a and PTEN. Our preliminary data demonstrate that in mouse and human hepatoma cells, a specific G9a inhibitor induces tumor suppressor genes, inhibits cell proliferation, and promotes apoptosis. In contrast, G9a-HKO mice appear normal, suggesting that loss of G9a in adult liver is well-tolerated. The central hypothesis is that G9a plays a key role in steatohepatitis and liver carcinogenesis via promoting lipogenesis and inhibiting tumor suppressor genes, and thus loss of G9a will inhibit hepatosteatosis and cell proliferation, whereas promote the apoptosis of liver cancer cells. This central hypothesis will be tested in two specific aims. Aim 1 will determine the importance of G9a in liver regeneration using models of 2/3 partial hepatectomy in G9a-HKO mice. The working hypothesis is that G9a-HKO mice will have relatively normal liver regeneration despite a moderate/minor delay in the regenerative process. Aim 2 will determine the importance of G9a in steatohepatitis and liver carcinogenesis using mice with hepatocyte-specific double knockout of PTEN and G9a. The working hypothesis is that loss of G9a will prevent PTEN-null-induced progression of hepatosteatosis-steatohepatitis to cirrhosis and liver cancer via inhibiting lipogenesis and cell proliferation whereas enhancing apoptosis. Results from this study will provide crucial novel knowledge about the importance of G9a in normal liver function, liver regeneration, and liver carcinogenesis, which may ultimately help to identify G9a inhibitor as a novel epigenetic drug for the prevention and treatment of liver cancer, a deadly disease with increasing incidence in the USA.

描述(由申请人提供)：长期的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。表观遗传学异常是肝细胞癌发生的主要标志。肝细胞中肿瘤抑制因子磷酸酶和张力蛋白同源物(PTEN)的缺失导致进行性脂肪性肝炎和肝癌；PTEN和其他肿瘤抑制因子的表观遗传沉默与组蛋白H3在赖氨酸-9(H3K9me2)的二甲基化有关，H3K9me2是基因沉默的关键抑制标记。组蛋白甲基转移酶G9a通过催化H3K9me2和通过DNA甲基转移酶促进DNA甲基化，在胚胎发育中发挥关键作用。G9a通过一组在脂肪性肝炎和癌症发生中起重要作用的转录抑制因子/辅助抑制因子来调节基因抑制。G9a基因的敲除导致端粒逆转录酶的显著下调和癌细胞的凋亡。G9a在人肝癌中被诱导；然而，关于G9a在肝脏病理生理和癌变中的体内重要性，人们知之甚少，这主要是由于G9a缺失的小鼠的胚胎致死性。本研究的目的是利用新的肝细胞特异性G9a和PTEN基因敲除小鼠模型，阐明G9a在肝脏中的病理生理学意义。我们的初步数据表明，在小鼠和人肝癌细胞中，一种特异性的G9a抑制剂诱导肿瘤抑制基因，抑制细胞增殖，并促进细胞凋亡。相比之下，G9a-HKO小鼠看起来正常，这表明成人肝脏中G9a的丢失是可以容忍的。中心假说是G9a通过促进脂肪生成和抑制抑癌基因在脂肪性肝炎和肝癌的发生中起关键作用，因此G9a的缺失将抑制肝骨病和细胞增殖，促进肝癌细胞的凋亡。这一核心假设将在两个具体目标上得到检验。目的1利用G9a-HKO小鼠2/3肝部分切除模型，确定G9a在肝再生中的重要性。工作假设是，G9a-HKO小鼠将有相对正常的肝脏再生，尽管再生过程有适度/轻微的延迟。目的2利用肝细胞特异性PTEN和G9a双基因敲除小鼠，确定G9a在脂肪性肝炎和肝癌发生中的重要性。工作假设是，G9a的缺失将通过抑制脂肪生成和细胞增殖，促进细胞凋亡，防止PTEN缺失诱导的肝脏骨质疏松症-脂肪性肝炎进展为肝硬变和肝癌。这项研究的结果将为G9a在正常肝功能、肝再生和肝癌发生中的重要性提供关键的新知识，最终可能有助于确定G9a抑制剂作为一种新的表观遗传学药物用于预防和治疗肝癌，肝癌是一种在美国发病率不断上升的致命疾病。