(PQA1) Novel epigenetic mechanism mediate metformin inhibition of prostate cancer

(PQA1) 新的表观遗传机制介导二甲双胍抑制前列腺癌

基本信息

批准号：
9066594
负责人：
Xin Li
金额：
$ 30.74万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066594
关键词：
Affect American Androgen Receptor Antineoplastic Agents Apoptosis Area Binding Bone Marrow Bone Resorption CXC Chemokines CXCL12 gene CXCR4 gene Cancer Cell Growth Cancer Etiology Cell Cycle Progression Cell Line Cell Proliferation Cells Cessation of life ChIP-on-chip DNA Methylation DNA Modification Methylases DNA Sequence Data Deacetylase Diabetes Mellitus Down-Regulation Drug usage Enzyme-Linked Immunosorbent Assay Enzymes Epidemiology Epidermal Growth Factor Epigenetic Process Epithelial Event FDA approved FRAP1 gene Gene Expression Gene Targeting Genes Goals Growth Health Histology Histone Deacetylase Homologous Gene Human Hypoglycemic Agents Immunoprecipitation In Vitro Injection of therapeutic agent Insulin Insulin-Like Growth Factor I Knowledge Ligands Malignant neoplasm of prostate Measures Mediating Mesenchymal Metastatic Neoplasm to the Bone Metformin Methylation Methyltransferase MicroRNAs Migration Assay Modification Molecular Mus Neoplasm Metastasis Neoplasms Non-Insulin-Dependent Diabetes Mellitus Oral Osteoclasts Outcome Pathway interactions Play Property Prostate Prostatic Neoplasms Proteins Risk Role SET Domain Second Primary Cancers Serum Shapes Sirolimus Snails Staining method Stains TRANCE protein Testing Testosterone Tissue Microarray Tissues Tumor Suppressor Proteins Up-Regulation VEGFA gene Western Blotting Work Xenograft Model antitumor effect base bone cancer therapy cell growth cell motility chemokine chromatin immunoprecipitation diabetic patient epigenetic regulation histone modification in vivo in vivo Model insight men neoplastic novel outcome forecast overexpression prostate cancer cell receptor expression research study survivin targeted treatment tibia tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths in American men. The overarching goal of this proposal is to elucidate a novel molecular mechanism that mediates metformin anti-tumor efficacy through epigenetic alterations in prostate cancer. Our strong in vitro and in vivo preliminary data demonstrated that metformin reduces expression of methyltransferase Suv39H1 and interaction with histone deacetylase Sirt1. Metformin further reduces the methylation levels of tumor suppressor microRNA (miR)-1, reduces androgen receptor (AR) expression, reduces prostate cancer cell migration, and inhibits expression of genes that favor prostate cancer skeletal metastasis in bone marrow. Based on our preliminary data we hypothesize that metformin inhibits prostate cancer growth and metastasis via epigenetic machinery mediated by Suv39H1, Sirt1 and miR1 targeting both tumor and its microenvironment. To test our hypothesis we propose three integrated specific aims: Aim 1 is to elucidate the molecular events mediated through metformin-regulated methyltransferase Suv39H1 in restricting prostate tumor growth. We will use different Suv39H1 levels or Suve39H1 lacking SET domain: Suv39H1- null, Suv39H1?SET and over-expressing cells, to determine AR expression and Sirt1-Suv39H1 binding is affected by downregulation of Suv39H1 by metformin to suppress prostate cancer cell growth and epithelial- mesenchymal transition (EMT). Aim 2 is to elucidate the molecular events mediated by metformin up- regulation of miR-1 in restricting prostate tumor growth. miR-1 methylation levels and its expression will be measured with treatment of metformin or vehicle, in the cell lines expressing different levels of Suv39H1 generated in Aim 1. Hi-Myc prostate cancer mice treated with treated with metformin or vehicle will be used to confirm the metformin up-regulation of miR-1 in vivo. Aim 3 is to elucidate the molecular mechanism by which metformin targets bone microenvironment to restrict bone metastasis. We will use miR-1- overexpressing or silenced prostate cancer cells and in vivo model to determine the levels of CXCR4/CXCL12 and miR-1 in prostate cancer tissues. Intra-tibia injections of miR-1-null or -overexpressed C4-2b cells will be used to determine the miR-1 mediates metformin suppression of prostate cancer growth in bone. Accomplishment of the experiments outlined in this proposal will determine the molecular mechanism of metformin on epigenetic regulations of prostate cancer. More recent findings suggest that metformin has anti neoplastic properties and our study will reveal important gaps in current knowledge about role of metformin in controlling prostate cancer. The outcomes of our study are expected to have exceptionally high potential to re- shape current key concept and paradigms about the role of metformin in prostate cancer treatment.

描述（由申请人提供）：前列腺癌是美国男性最常见的癌症，也是癌症相关死亡的第二大原因。该提案的总体目标是阐明一种新型的分子机制，该机制通过前列腺癌的表观遗传改变介导二甲双胍抗肿瘤功效。我们强大的体外和体内初步数据表明，二甲双胍降低甲基转移酶SUV39H1的表达以及与组蛋白脱乙酰基酶SIRT1的相互作用。二甲双胍进一步降低肿瘤抑制microRNA（miR）-1的甲基化水平，降低雄激素受体（AR）的表达，降低前列腺癌细胞的迁移，并抑制骨髓中有利于前列腺癌骨骼转移的基因的表达。基于我们的初步数据，我们假设二甲双胍通过SUV39H1，SIRT1和MIR1介导的表观遗传机制抑制前列腺癌的生长和转移，靶向肿瘤及其微环境。为了检验我们的假设，我们提出了三个集成的特定目的：目标1是阐明通过二甲双胍调节的甲基转移酶SUV39H1介导的分子事件，以限制前列腺肿瘤的生长。 We will use different Suv39H1 levels or Suve39H1 lacking SET domain: Suv39H1- null, Suv39H1?SET and over-expressing cells, to determine AR expression and Sirt1-Suv39H1 binding is affected by downregulation of Suv39H1 by metformin to suppress prostate cancer cell growth and epithelial- mesenchymal transition (EMT).目的2是阐明由二甲双胍调节miR-1在限制前列腺肿瘤生长中介导的分子事件。 miR-1甲基化水平及其表达将通过二甲双胍或媒介物的处理来测量，在AIM 1中表达不同水平的SUV39H1的细胞系中。目的3是阐明二甲双胍靶向骨微环境限制骨转移的分子机制。我们将使用miR-1-过表达或沉默的前列腺癌细胞和体内模型来确定前列腺癌组织中CXCR4/CXCL12和miR-1的水平。对腹腔内注射miR-1-NULL或过表达的C4-2B细胞将用于确定miR-1介导骨中前列腺癌生长的二甲双胍抑制。该提案中概述的实验的完成将确定二甲双胍对前列腺癌表观遗传调节的分子机制。最近的发现表明，二甲双胍具有抗肿瘤特性，我们的研究将揭示有关二甲双胍在控制前列腺癌中作用的当前知识的重要差距。预计我们的研究结果将具有针对当前关键概念和有关二甲双胍在前列腺癌治疗中的作用的范式的极高潜力。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metformin inhibits salivary adenocarcinoma growth through cell cycle arrest and apoptosis.

DOI：
发表时间：
2015
期刊：
American journal of cancer research
影响因子：
5.3
作者：
Yuqi Guo;Tao Yu;Jian Yang;Tianqing Zhang;Yang Zhou;F. He;Z. Kurago;D. Myssiorek;Yingjie Wu;Peng Lee;Xin Li
通讯作者：
Yuqi Guo;Tao Yu;Jian Yang;Tianqing Zhang;Yang Zhou;F. He;Z. Kurago;D. Myssiorek;Yingjie Wu;Peng Lee;Xin Li

Metformin Improves Diabetic Bone Health by Re-Balancing Catabolism and Nitrogen Disposal.