Epigenetic regulation of cancer metabolism by G9A

G9A 对癌症代谢的表观遗传调控

基本信息

批准号：
9323351
负责人：
HAN-FEI DING
金额：
$ 31.54万
依托单位：
AUGUSTA UNIVERSITY
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：
2014-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9323351
关键词：
Anabolism Binding Biochemical Reaction Biological Assay Cancer Cell Growth Cell Proliferation Coenzymes DNA Binding DNA Binding Domain Dependence Drug Targeting Epigenetic Process Flavin-Adenine Dinucleotide Genes Genetic Transcription Glycine Goals Growth Histone H3 Histone-Lysine N-Methyltransferase Histones Human Investigation KDM1A gene Lead Lysine MYCN gene Malignant Neoplasms Membrane Lipids Metabolic Metabolism Methylation Methyltransferase Modeling Molecular Molecular Target Nucleic Acids Outcome Pathway interactions Production Proteins Recruitment Activity Regulation Research Role S-Adenosylmethionine Serine Starvation Testing Transactivation Transcriptional Activation Transcriptional Regulation anticancer research cancer cell demethylation epigenetic regulation macromolecule methyl group novel drug class overexpression promoter public health relevance response targeted cancer therapy transcription factor tumor metabolism

项目摘要

DESCRIPTION (provided by applicant): Cancer cells reprogram their metabolism to meet the biosynthetic challenge of growth and proliferation. How cancer metabolism is initiated and maintained in cancer cells is a central question of cancer research. Recent studies demonstrate that increased activation of the serine-glycine synthesis pathway, which generates many biosynthetic precursors and metabolites essential for the production of proteins, lipid membranes and nucleic acids, is an integral part of cancer metabolism. We recently uncovered an essential role of the histone H3 lysine 9 (H3K9) methyltransferase G9A in epigenetic activation of this biosynthesis pathway. G9A has a primary role in catalyzing H3K9 monomethylation and dimethylation (H3K9me1 and H3K9me2), with H3K9me1 being an active mark and H3K9me2 being a repressive mark. G9A overexpression has been observed in many types of human cancers. We found that G9A transcriptionally activates serine-glycine synthesis by increasing H3K9me1 at the promoters of the pathway genes. The proposed research is to determine 1) how G9A is specifically targeted to the pathway genes, given that G9A has no sequence-specific DNA-binding domain, and 2) how G9A specifically marks these genes with H3K9me1, given that G9A can catalyze both H3K9me1 and H3K9me2. In Aim 1, we will investigate the sequence-specific DNA-binding transcription factor ATF4 as a mechanism for targeting G9A to the promoters of the serine pathway genes. We will determine whether ATF4 is required for G9A to bind to these promoters, to modulate their H3K9 methylation states, and to increase glycolic flux for serine-glycine synthesis. We will also investigate the molecular basis o the G9A-ATF4 interaction. In Aim 2, we will investigate the transcription factor MYCN as an alternative mechanism for targeting G9A to the serine pathway genes, particularly in cancer cells with G9A overexpression. We will determine whether MYCN is required for G9A to bind to these gene promoters, to modulate their H3K9 methylation states, and to increase glycolic flux for serine-glycine synthesis. We will also investigate the molecular basis of the G9A-MYCN interaction. In Aim 3, we will test the hypothesis that the H3K9 demethylase KDM4C, which specifically removes H3K9me2 and H3K9me3, cooperates with G9A to maintain high levels of H3K9me1 at these gene promoters. We will determine whether G9A and KDM4C bind simultaneously to these gene promoters and whether G9A requires KDM4C to maintain high-level H3K9me1 at these promoters for transcriptional activation. We will also investigate the molecular basis of the G9A-KDM4C cooperation. The proposed investigation is anticipated to identify a new regulatory mechanism for the control of serine-glycine synthesis and to introduce a new avenue to target cancer metabolism for therapy. Additionally, functional assays of

描述（由申请人提供）：癌细胞重新编程其代谢，以应对生长和增殖的生物合成挑战。癌细胞中癌症代谢的启动和维持是癌症研究的核心问题。最近的研究表明，丝氨酸 - 甘氨酸合成途径的激活增加，该途径产生许多生物合成前体和代谢物，对于蛋白质，脂质膜和核酸的产生必不可少，是癌症代谢的组成部分。最近，我们发现了组蛋白H3赖氨酸9（H3K9）甲基转移酶G9A在该生物合成途径的表观遗传激活中的重要作用。 G9A在催化H3K9单甲基化和二甲基化（H3K9ME1和H3K9ME2）中具有主要作用，而H3K9ME1是一个活跃的标记，而H3K9ME2是一种抑制标记。在许多类型的人类癌症中已经观察到了G9A过表达。我们发现，G9A转录通过在途径基因的启动子处增加H3K9ME1来激活丝氨酸 - 甘氨酸的合成。拟议的研究是确定1）鉴于G9A没有序列特异性的DNA结合结构域，以及2）G9A如何用H3K9ME1特异性地标记了这些基因，因为G9A如何用G9A催化H3K9ME1和H3K9ME2，G9A如何特异性地标记了这些基因。在AIM 1中，我们将研究序列特异性的DNA结合转录因子ATF4，作为将G9A靶向丝氨酸途径基因启动子的机制。我们将确定G9A是否需要ATF4与这些启动子结合，调节其H3K9甲基化态，并增加丝氨酸 - 甘氨酸合成的糖基氧气。我们还将研究G9A-ATF4相互作用的分子基础。在AIM 2中，我们将研究转录因子MYCN，作为将G9A靶向丝氨酸途径基因的替代机制，尤其是在G9A过表达的癌细胞中。我们将确定是否需要MYCN与G9A结合这些基因启动子，调节其H3K9甲基化态，并增加丝氨酸 - 甘氨酸合成的糖尿氧气。我们还将研究G9A-MYCN相互作用的分子基础。在AIM 3中，我们将检验以下假设：H3K9脱甲基酶KDM4C专门删除了H3K9ME2和H3K9ME3，它与G9A合作以维持这些基因启动子的高水平的H3K9ME1。我们将确定G9A和KDM4C是否与这些基因启动子同时结合，以及G9A是否要求KDM4C在这些启动子上维持高级H3K9ME1进行转录激活。我们还将研究G9A-KDM4C合作的分子基础。预计拟议的研究将确定一种新的调节机制，以控制丝氨酸 - 甘氨酸合成，并引入新的途径，以靶向癌症代谢进行治疗。另外，功能测定