A non-canonical role for EZH2 in rRNA methtlation

EZH2 在 rRNA 甲基化中的非典型作用

基本信息

批准号：
10448517
负责人：
Qi Cao
金额：
$ 42.01万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448517
关键词：
Affect American Binding Biological Markers Cancer Etiology Cancer Patient Cell Line Cell Maintenance Cessation of life Clinic Clinical Complex DNA Methylation Data Development Disease EZH2 gene Endoderm Epigenetic Process Glutamine Histone H2A Histone H3 Histone-Lysine N-Methyltransferase Histones In Vitro Internal Ribosome Entry Site Lesion Lysine Malignant Neoplasms Malignant neoplasm of prostate Mediating Messenger RNA Methylation Methyltransferase MicroRNAs Modification Molecular Mus Neoplasm Metastasis Oncogenes Oncogenic Organoids Outcome Patients Peptide Synthesis Play Polycomb Polyribosomes Protein Biosynthesis Proteins RNA RNA Editing RNA methylation RNA, Ribosomal, 28S Radiation therapy Regulation Reporting Ribonucleoproteins Ribose Ribosomal RNA Ribosomes Role Site Small Nucleolar RNA Small Nucleolar Ribonucleoproteins Survival Analysis TP53 gene Testing Tissue Sample Transcript Transcription Repressor Transfer RNA Translation Initiation Translations Untranslated RNA Work Xenograft Model advanced prostate cancer base cancer initiation cancer type castration resistant prostate cancer chemotherapy demethylation epigenetic regulation fibrillarin gain of function mutation histone methyltransferase histone modification in vivo inhibitor insight knock-down malignant breast neoplasm men novel novel therapeutics overexpression particle patient population polysome profiling prostate cancer cell prostate cancer progression recruit ribosome profiling stem cells tumor progression

项目摘要

Background: Mounting evidence suggests that dysregulated epigenetic modifications play a crucial role in cancer initiation, progression, and metastasis. Epigenetic regulations include histone modifications, DNA methylation and demethylation, regulations through microRNA and long non-coding RNAs (lncRNAs), and RNA methylation and editing. RNA methylation occurs on all messenger RNA (mRNA), transfer RNA (tRNA) and ribosome RNA (rRNA). Compared to the recent advances in understanding mRNA methylation, the function of rRNA methylation is understudied. The epigenetic modifier Polycomb group protein EZH2, a well-known oncogenic histone lysine methyltransferase for H3K27 methylation and a key component of Polycomb Repressive Complex 2 (PRC2), is upregulated in cancer and is a biomarker of aggressive cancers. Our preliminary data show that EZH2 directly interacts with FBL (Fibrillarin), the only characterized rRNA 2’-O-ribose methyltransferase, and regulates rRNA 2’-O-methylation levels. Knocking down EZH2 alters FBL-mediated nascent peptide synthesis, IRES-driven protein translation initiation, and other ribosomal functions. Importantly, our data reveal that FBL is upregulated in PCa, and EZH2highFBLhigh PCa patients had worse clinic outcomes compared to other patients. Objective/Hypothesis: Our overall hypotheses are that EZH2 plays dual roles in PCa, a canonical role as histone methyltransferase and a non-canonical role by directly interacting with FBL and then regulating rRNA methylation and ribosomal functions. Further, this novel EZH2 function is independent of the PRC2 complex and its lysine methyltransferase activity. Overexpression of EZH2 and FBL together will promote PCa progression. Based on our preliminary data, we propose the following specific aims to test our hypotheses. Specific Aim 1: To investigate how EZH2 regulates the assembly of box C/D snoRNP. Specific Aim 2: To characterize the non-canonical functions of EZH2 in rRNA methylation and protein synthesis through its interaction with FBL in vitro. Specific Aim 3: To examine the EZH2-FBL interaction and EZH2’s novel functions in vivo. Impact: This work will dissect how EZH2 performs its dual role in cancer progression through its canonical function as a H3K27 methyltransferase and a non-canonical function in rRNA methylation via FBL.

背景：越来越多的证据表明，失调的表观遗传修饰在癌症的发生、进展和转移包括组蛋白修饰、DNA。甲基化和去甲基化，通过 microRNA 和长非编码 RNA (lncRNA) 进行调节，以及 RNA 甲基化和编辑发生在所有信使 RNA (mRNA)、转移 RNA (tRNA) 上。与理解 mRNA 甲基化的最新进展相比， rRNA 甲基化的功能尚待研究。表观遗传修饰剂 Polycomb 组蛋白 EZH2，一种著名的致癌组蛋白赖氨酸用于 H3K27 甲基化的甲基转移酶和 Polycomb 抑制复合物 2 (PRC2) 的关键成分是我们的初步数据表明，EZH2 在癌症中表达上调，是侵袭性癌症的生物标志物。与唯一表征的 rRNA 2'-O-核糖甲基转移酶 FBL（纤维蛋白）相互作用，并调节 rRNA 2’-O-甲基化水平降低 EZH2 会改变 FBL 介导的新生肽合成（IRES 驱动）。重要的是，我们的数据表明 FBL 被上调。在 PCa 中，与其他患者相比，EZH2highFBLhigh PCa 患者的临床结果更差。目标/假设：我们的总体假设是 EZH2 在 PCa 中发挥双重作用，这是一种典型的作用作为组蛋白甲基转移酶并通过直接与 FBL 相互作用发挥非典型作用，然后此外，这种新的 EZH2 功能是调节 rRNA 甲基化和核糖体功能。独立于 PRC2 复合体及其赖氨酸甲基转移酶活性。和 FBL 一起将促进 PCa 进展。根据我们的初步数据，我们提出以下具体目标来检验我们的假设。具体目标 1：研究 EZH2 如何调节 box C/D snoRNP 的组装。具体目标 2：表征 EZH2 在 rRNA 甲基化和蛋白质中的非典型功能通过与 FBL 的体外相互作用进行合成。具体目标 3：检查 EZH2-FBL 相互作用以及 EZH2 在体内的新功能。影响：这项工作将剖析 EZH2 如何通过其规范在癌症进展中发挥双重作用作为 H3K27 甲基转移酶发挥作用，并通过 FBL 在 rRNA 甲基化中发挥非规范功能。