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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：
10181998
负责人：
Binhua P Zhou
金额：
$ 39.39万
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/10181998
关键词：
Acetylation Aging Anchorage-Independent Growth Animal Model 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 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 Research Respiration Rodent Role Signal Pathway Site Specimen Suspensions Talents Testing Therapeutic Transcriptional Regulation Up-Regulation Vertebral column Xenograft Model arginine methyltransferase base breast cancer progression coactivator-associated arginine methyltransferase 1 druggable target experimental study extracellular in vivo inhibitor/antagonist 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 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+ 挽救途径中的关键酶，其功能尚不明确。在基底样乳腺癌 (BLBC) 中高特异性表达。我们发现 NNMT 是稳健的当 BLBC 细胞脱离基质并在悬浮液中生长时，该值升高。不仅是NNMT的淘汰赛（KO）抑制体外不依赖贴壁的生长，还抑制动物体内的肿瘤生长和转移模型。通过无偏倚的 CRISPR-Cas9 文库筛选，我们将 FOXC1-CARM1 复合物鉴定为负责 BLBC 中 NNMT 的上调。重要的是，通过 KO 或使用抑制剂增加化疗药物介导的促凋亡作用。因此我们假设 NNMT 是维持 BLBC 进展和转移 NAD+ 稳态的关键守门人；这种稳态增强细胞抗氧化防御机制，并防止 BLBC 细胞遇到的 ROS 激增转移期间。该提案的目标是 (1) 表征 NNMT 在调节 NAD+ 中的功能肿瘤进展和转移中的稳态； (2) 描述 NNMT 的转录调控 FOXC1-CARM1 复合体； (3) 探索 NNMT 作为预后生物标志物和预测的临床价值 BLBC 的可药物靶标。在强有力的初步数据的指导下，我们将通过追求三个方面来检验这一假设具体目标：（1）确定NNMT在BLBC中的关键作用； (2) 描述 NNMT 转录 FOXC1-CARM1 复合体； (3) 明确 NNMT 在乳腺发育中的作用乳腺癌转移。我们的提议是创新且意义重大的，因为 NNMT 代表了阿基里斯 BLBC 的跟部；针对这种代谢脆弱性提供了针对转移性癌症的有效治疗选择 BLBC。