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Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis

明确 NNMT 在乳腺癌进展和转移中的关键功能和调节

基本信息

批准号：
10606561
负责人：
Binhua P Zhou
金额：
$ 38.61万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606561
关键词：
Acetylation Aging Anchorage-Independent Growth Animal Model Apoptotic Brain Breast Cancer Cell Breast cancer metastasis CRISPR library Cancer Biology Cancer Cell Growth Cell Nucleus Cell model Clinical Code Complex Cytoplasm Data Development Diabetes Mellitus Diagnosis Disease Drug resistance Endowment Environment Enzymes Event Exhibits Extravasation FOXC1 gene Family Gatekeeping Genetic Transcription Goals Homeostasis Human In Vitro Knock-out Lung Malignant Neoplasms Mammary gland Mediating Metabolic Metabolic Pathway Metabolism Methyltransferase Mitochondria NADH NADP Neoplasm Metastasis Niacinamide Nicotinamide N-Methyltransferase Nicotinamide adenine dinucleotide Oncogenic Oxidation-Reduction Oxidative Stress Pathologist Pathway interactions Pharmaceutical Preparations Pharmacotherapy Positioning Attribute Prognosis Prognostic Marker Proliferating Property Reactive Oxygen Species Regimen Regulation Rejuvenation Research Respiration Rodent Role Shapes Signal Pathway Site Specimen Suspensions Talents Testing Therapeutic Transcriptional Regulation Tumor Promotion Up-Regulation Vertebral column Xenograft Model arginine methyltransferase breast cancer progression coactivator-associated arginine methyltransferase 1 druggable target experimental study extracellular in vivo inhibitor innovation knock-down malignant breast neoplasm mammary gland development metabolomics mouse model multidisciplinary novel therapeutic intervention oxidative damage patient derived xenograft model prevent screening stem-like cell success synergism therapeutically effective therapy resistant transcription factor tumor growth tumor progression uptake

项目摘要

N-methyltransferase (NNMT), a key enzyme in the NAD+ salvage pathway with unclear functions, is expressed highly and specifically in basal-like breast cancer (BLBC). We found that NNMT is robustly elevated when BLBC cells detach from a matrix and grow in suspension. Knockout (KO) of NNMT not only inhibits anchorage-independent growth in vitro but also suppresses tumor growth and metastasis in animal models. Using an unbiased CRISPR-Cas9 library screening, we identified the FOXC1-CARM1 complex as being responsible for NNMT upregulation in BLBC. Importantly, inhibition of NNMT by either KO or use of an inhibitor increases the proapoptotic effects mediated by chemo-drugs. We thus hypothesize that NNMT is a critical gatekeeper that maintains NAD+ homeostasis for BLBC progression and metastasis; this homeostasis boosts the cellular antioxidative defense machinery, and prevents surges of ROS that BLBC cells encounter during metastasis. The objective of this proposal is to (1) characterize NNMT function in regulating NAD+ homeostasis in tumor progression and metastasis; (2) delineate the transcriptional regulation of NNMT by the FOXC1-CARM1 complex; and (3) explore the clinical value of NNMT as a prognostic biomarker and a druggable target for BLBC. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to determine the critical roles of NNMT in BLBC; (2) to delineate NNMT transcription by the FOXC1-CARM1 complex; and (3) to define the roles of NNMT in the development of mammary gland and breast cancer metastasis. Our proposal is innovative and significant, because NNMT represents the achilles heel of BLBC; targeting this metabolic vulnerability offers an effective therapeutic option against metastatic BLBC.

N-甲基转移酶（NNMT）是NAD+补救途径中的关键酶，功能尚不清楚，在基底细胞样乳腺癌（BLBC）中特异性高表达。我们发现NNMT是鲁棒的当BLBC细胞从基质中分离并在悬浮液中生长时升高。NNMT的敲除（KO）不仅在体外抑制非贴壁依赖性生长，但在动物中也抑制肿瘤生长和转移模型使用无偏的CRISPR-Cas9文库筛选，我们将FOXC 1-CARM 1复合物鉴定为负责BLBC中NNMT的上调。重要的是，通过KO或使用免疫抑制剂来抑制NNMT，抑制剂增加了化疗药物介导的促凋亡作用。因此，我们假设NNMT是一个维持BLBC进展和转移的NAD+稳态的关键守门人;这种稳态增强细胞的抗氧化防御机制，并防止BLBC细胞遇到的ROS激增在转移过程中。本提案的目的是（1）表征NNMT调节NAD+的功能肿瘤进展和转移中的稳态;（2）描述NNMT的转录调控， FOXC 1-CARM 1复合物;和（3）探索NNMT作为预后生物标志物的临床价值， BLBC的药物目标。在强有力的初步数据的指导下，我们将通过以下三个方面来检验这一假设：具体目标：（1）确定NNMT在BLBC中的重要作用;（2）通过BLBC中的NNMT转录来描述NNMT转录。研究NNMT在乳腺发育中的作用，乳腺癌转移我们的建议是创新的，意义重大，因为NNMT代表了阿基里斯 BLBC的脚跟;靶向这种代谢脆弱性提供了一种有效的治疗选择， BLBC。