Mitochondrial and nuclear functions of NKX3.1 in regulating oxidative stress in prostate cancer

NKX3.1在调节前列腺癌氧化应激中的线粒体和核功能

基本信息

批准号：
10528455
负责人：
Cory Abate-Shen
金额：
$ 37.93万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528455
关键词：
8p21 Biological Cancerous Cell Nucleus Cell physiology Cells Chromosome Mapping Clinical Clinical Research Complement DNA Damage Data Early Diagnosis Epithelium Equilibrium Event Evolution Gatekeeping Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Homeobox Genes Homeodomain Proteins Human Human Chromosomes Impairment Inflammation Intervention Investigation Knowledge Link Loss of Heterozygosity Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mediating Mitochondria Modeling Molecular NKX3-1 gene Nuclear Oxidative Regulation Oxidative Stress Physiological Process Prognosis Prostate Prostatic Epithelium Prostatic Intraepithelial Neoplasias Publishing Reactive Oxygen Species Regulation Research Role Specific qualifier value Stress Tissues Transcription Regulatory Protein Work assault cancer initiation cancer prevention cancer therapy cell growth regulation efficacy testing improved inhibitor loss of function novel preclinical study prostate cancer model response stem cells transcription factor tumor progression

项目摘要

Project Summary/Abstract We have been studying the processes associated with prostate differentiation and their relationship to prostate cancer through our investigations of the NKX3.1 homeobox gene, which is a master regulator of prostate epithelial specification that protects the prostatic epithelium from assaults associated with cancer initiation, including oxidative stress. Our investigations have now revealed that NKX3.1 defends prostate cells from oxidative stress by regulating gene expression in both the nucleus and mitochondria. We find that, in addition to its expected functions as a transcriptional factor in the nucleus, NKX3.1 also localizes to mitochondria in response to oxidative stress, where it regulates the expression of mitochondrial-encoded genes that control reactive oxygen species (ROS). Thus, we hypothesize that NKX3.1 regulates oxidative stress via its coordinated functions in nuclei and mitochondria, and that these functions are necessary to maintain prostate epithelial differentiation and suppress cancer initiation. Since relatively few nuclear transcriptional regulatory proteins have been shown to function in mitochondria, our studies provide a unique opportunity to understand how a tissue-specific transcription factor can control oxidative stress in different sub- cellular compartments, and the relevance of these activities for cancer. In Aim 1, we will investigate the functions of NKX3.1 in the nucleus for protection from oxidative stress and promotion of differentiation. We will investigate: (i) nuclear transcriptional regulatory functions of NKX3.1 for protection against oxidative stress; (ii) their relevance for prostate epithelial differentiation and cancer; and (iii) whether and if so how these functions impact mitochondrial function. In Aim 2, we will investigate novel functions of NKX3.1 in mitochondria. Based on our preliminary data showing that, in response to oxidative stress, NKX3.1 becomes localized to mitochondria where it regulates the expression of mitochondrial-encoded genes, we will investigate: (i) the mechanisms associated with localization of NKX3.1 to mitochondria; (ii) the mechanisms by which NKX3.1 regulates mitochondrial-encoded genes, particularly in comparison with its regulation of nuclear genes; and (iii) the importance of these mitochondrial-specific functions of NKX3.1 for regulation of oxidative stress and cellular differentiation. In Aim 3, we will complement these mechanistic studies by performing co-clinical studies to evaluate the relevance of regulation of oxidative stress by NKX3.1 for suppression of prostate cancer, and whether these activities can be targeted for cancer prevention using genetically-engineered mouse models and a human prostate tissue organotypic model. Relevance for PAR-17-203: Our proposed studies provide a unique opportunity to elucidate molecular mechanisms that govern the balance between oxidative stress and differentiation and cancer initiation and how these are coordinated between the nucleus and mitochondria.

项目摘要/摘要我们一直在研究与前列腺分化相关的过程及其与它们与前列腺癌通过我们对NKX3.1同型基因的调查，该基因是前列腺上皮规范保护前列腺上皮免受与癌症相关的攻击起始，包括氧化应激。我们的调查现在揭示了NKX3.1捍卫前列腺细胞通过调节核和线粒体中的基因表达来调节氧化应激。我们发现，在 NKX3.1的预期功能作为核中的转录因子的功能，还位于线粒体响应氧化应激，它调节线粒体编码的表达控制活性氧（ROS）的基因。因此，我们假设NKX3.1调节氧化通过其在核和线粒体中的协调功能进行压力，并且这些功能对于维持前列腺上皮分化并抑制癌症的开始。由于相对较少的核转录调节蛋白已显示在线粒体中起作用，我们的研究提供了独特的有机会了解组织特异性转录因子如何控制不同亚下的氧化应激细胞室，以及这些活动与癌症的相关性。在AIM 1中，我们将研究NKX3.1在核中的功能，以防止氧化应激。和促进分化。我们将研究：（i）NKX3.1的核转录调节功能防止氧化应激；（ii）它们与前列腺上皮分化和癌症的相关性；和（iii）这些功能是否以及如何影响线粒体功能。在AIM 2中，我们将研究小说 NKX3.1在线粒体中的功能。根据我们的初步数据，表明，响应氧化压力，nkx3.1局部在线粒体上调节线粒体编码的表达基因，我们将研究：（i）与线粒体NKX3.1定位相关的机制；（ii） NKX3.1调节线粒体编码基因的机制，特别是与其相比核基因的调节；（iii）NKX3.1的这些线粒体特异性功能的重要性调节氧化应激和细胞分化。在AIM 3中，我们将补充这些机制通过进行共同研究研究来评估NKX3.1对氧化应激调节的相关性的研究。为了抑制前列腺癌，以及这些活动是否可以针对预防癌症遗传工程的小鼠模型和人类前列腺组织器官模型。与PAR-17-203的相关性：我们提出的研究为阐明分子提供了独特的机会控制氧化应激与分化与癌症开始之间平衡的机制以及如何这些在细胞核和线粒体之间进行了协调。