RNA epigenetic regulation of cancer metabolism

RNA表观遗传调控癌症代谢

• 批准号: 10207521
• 负责人: HAN-FEI DING
• 金额: $ 3.23万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207521
• 关键词: Address; Amino Acids; Award; Biological; Biological Models; Biological Process; Cancer Control; Cancer cell line; Carbon; Cell Proliferation; Cells; Complement 5a; Development; Enzymes; Epigenetic Process; Event; Experimental Models; Family; Genetic Transcription; Glycine; Goals; Growth; Histone-Lysine N-Methyltransferase; Human; Hydrogen Bonding; Light; Link; MYC gene; MYC-Family Oncogene; MYCN gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Control; Metabolism; Modeling; Modification; Molecular; Oncogene Activation; Pseudouridine; Publications; RNA; Regulation; Research; Role; Rotation; Serine; Signal Transduction; Site; Stress; Structure; Testing; Therapeutic; Transcription Coactivator; Translations; Uracil; Uridine; anticancer research; base; biological adaptation to stress; cancer cell; cancer therapy; dietary; druggable target; epigenetic regulation; knock-down; mRNA Stability; new therapeutic target; novel; stable isotope; sugar; targeted cancer therapy; tumor; tumor metabolism; tumorigenesis

The proposed research is to investigate a new epigenetic mechanism for the control of metabolic reprogramming in cancer cells. Pseudouridylation is a common epigenetic modification of human mRNA, which is catalyzed by the family of pseudouridine synthases (PUS) that convert uridine to pseudouridine via base- specific isomerization. The molecular and functional consequences of mRNA pseudouridylation are poorly understood. A major barrier is the lack of suitable and robust experimental models to study the function and regulation of mRNA pseudouridylation. We approached this problem by focusing on the PUS family of enzymes in cancer. Our preliminary studies revealed that the expression of one of the enzymes, PUS7, is transcriptionally upregulated by the oncogenes MYC and MYCN, which are commonly activated in various types of human cancers. Increased expression of PUS7 promotes cancer cell proliferation and tumorigenesis. A key downstream target of PUS7 is ATF4, a master regulator of stress responses and cellular metabolism, which is also targeted by MYCN in reprogramming cellular metabolism to sustain cancer cell proliferation. PUS7 catalyzes pseudouridylation at specific sites in ATF4 mRNA and upregulates ATF4 expression. Based on these findings, we hypothesize that PUS7 is an effector of MYC/MYCN in cancer metabolic reprogramming by boosting ATF4 expression via ATF4 mRNA pseudouridylation. We further hypothesize that this PUS7-ATF4 axis has a key role in the control of stress-induced metabolic reprogramming. The proposed research will test these hypotheses. Aim 1 studies will be focused on the biological relevance of PUS7-dependent ATF4 mRNA pseudouridylation in the model system of stress responses. We will define the molecular mechanism by which PUS7-dependent ATF4 mRNA pseudouridylation increases ATF4 expression (Aim 1.1). We will determine if PUS7-dependent ATF4 mRNA pseudouridylation is regulated by stress signals and is required for stress induction of ATF4 (Aim 1.2). We will determine if PUS7 controls stress-induced metabolic reprogramming by regulating ATF4 expression (Aim 1.3). Aim 2 studies will be focused on the cancer relevance of PUS7-dependent ATF4 mRNA pseudouridylation using MYC/MYCN cancer cell lines and tumor models. We will determine if PUS7 is an effector of MYC/MYCN in metabolic reprogramming (Aim 2.1). We will determine whether PUS7-mediated ATF4 mRNA pseudouridylation is regulated by MYC/MYCN and is an epigenetic event during MYC-driven tumor development (Aim 2.2). We will investigate if PUS7 knockdown creates a metabolic vulnerability in MYC/MYCN-driven tumors that could be exploited for cancer therapy (Aim 2.3). Successful completion of this project will shed light on the biological function and cancer relevance of PUS7-dependent mRNA pseudouridylation, which might be exploited for better cancer treatment.

拟议的研究是研究一种新的表观遗传机制，以控制代谢 在癌细胞中重新编程。伪苷化是人mRNA的常见表观遗传修饰，它 被假喹啉合酶（PU）催化 特定的异构化。 mRNA伪苷化的分子和功能后果较差 理解。一个主要的障碍是缺乏适当且可靠的实验模型来研究该功能和 mRNA伪苷化的调节。我们通过专注于脓液家族来解决这个问题 癌症中的酶。我们的初步研究表明，其中一种酶Pus7的表达是 在转录上被癌基因MYC和MYCN上调，这些通常在各种中被激活 人类癌症类型。 PUS7的表达增加会促进癌细胞的增殖和肿瘤发生。 PUS7的关键下游目标是ATF4，ATF4是应力反应和细胞代谢的主要调节剂， MYCN也针对重编程细胞代谢以维持癌细胞增殖。 PUS7在ATF4 mRNA中的特定位点催化假基因化并上调ATF4表达。基于 在这些发现中，我们假设PUS7是癌症代谢中MYC/MYCN的效应子 通过ATF4 mRNA伪苷化来增强ATF4表达来重新编程。我们进一步 假设该PUS7-ATF4轴在控制压力诱导的代谢中具有关键作用 重新编程。拟议的研究将检验这些假设。 AIM 1研究将集中于 PUS7依赖性ATF4 mRNA伪啶在压力系统中的生物学相关性 回答。我们将定义PUS7依赖性ATF4 mRNA的分子机制 伪基化增加了ATF4表达（AIM 1.1）。我们将确定PUS7依赖性ATF4 mRNA是否 伪苷化受应力信号调节，是ATF4应力诱导所必需的（AIM 1.2）。我们将 确定PUS7是否通过调节ATF4表达来控制应力诱导的代谢重编程（AIM 1.3）。 AIM 2研究将集中于PUS7依赖性ATF4 mRNA伪苷化的癌症相关性 使用MYC/MYCN癌细胞系和肿瘤模型。我们将确定PUS7是否是MYC/MYCN的效应子 在代谢重编程中（AIM 2.1）。我们将确定PUS7介导的ATF4 mRNA是否 伪啶基受到MYC/MYCN的调节，是MYC驱动肿瘤期间的表观遗传事件 开发（目标2.2）。我们将调查PUS7敲低是否在 MYC/MYCN驱动的肿瘤可以用于癌症治疗（AIM 2.3）。成功完成 项目将阐明PUS7依赖性mRNA的生物学功能和癌症相关性 假基因化，可以利用以改善癌症治疗。