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，表观遗传修饰失调在癌症的启动，进展和转移。表观遗传法规包括组蛋白修饰，DNA 甲基化和脱甲基化，通过microRNA和长的非编码RNA（LNCRNA）和 RNA甲基化和编辑。 RNA甲基化发生在所有信使RNA（mRNA），转移RNA（tRNA）上和核糖体RNA（rRNA）。与最近理解mRNA甲基化的进展相比理解rRNA甲基化的功能。表观遗传修饰剂Polycomb蛋白EZH2，一种众所周知的致癌性组蛋白赖氨酸用于H3K27甲基化的甲基转移酶和Polycomb抑制复合物2（PRC2）的关键成分IS 在癌症中上调，是侵略性癌症的生物标志物。我们的初步数据表明EZH2直接与FBL（纤维林）相互作用，唯一表征的RRNA 2'-O-ribose甲基转移酶，并调节rRNA 2'-O-甲基化水平。击倒EZH2改变了FBL介导的新生胡椒合成，以IRES为导向的蛋白质翻译起始和其他核糖体功能。重要的是，我们的数据显示FBL已更新与其他患者相比，在PCA和EZH2HIGHFBLHIGH PCA患者的诊所结局较差。客观/假设：我们的总体假设是EZH2在PCA中扮演双重角色，这是一个规范的角色作为组蛋白甲基转移酶和非传统作用，直接与FBL相互作用，然后调节rRNA甲基化和核糖体功能。此外，这个新颖的EZH2功能是独立于PRC2复合物及其赖氨酸甲基转移酶活性。 EZH2的过表达 FBL一起促进PCA的进展。根据我们的初步数据，我们提出了以下特定目的来检验我们的假设。特定目的1：研究EZH2如何调节框C/D snornp的组件。特定目的2：表征EZH2在rRNA甲基化和蛋白质中的非规范功能通过在体外与FBL的相互作用进行合成。特定目标3：检查EZH2-FBL相互作用和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通过FBL作为H3K27甲基转移酶的H3K27甲基转移酶和非典型功能。