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

• 批准号: 10308021
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308021
• 关键词: 8p21; Biological; Cancerous; Cell Nucleus; Cell physiology; Cells; Clinical; Clinical Research; Complement; DNA Damage; Data; Early Diagnosis; Epithelial; Equilibrium; Event; Evolution; Gatekeeping; Gene Expression; Genes; Genetic Transcription; Genetically Engineered Mouse; Homeobox Genes; Homeodomain Proteins; Human; Human Chromosomes; Impairment; Inflammation; Intervention; Investigation; Knowledge; Lead; Link; Loss of Heterozygosity; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; 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; Stress; Tissues; Transcription Regulatory Protein; Work; assault; base; 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

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.

项目总结/摘要 我们一直在研究与前列腺分化相关的过程及其与前列腺癌的关系。 通过我们对NKX3.1同源框基因的研究，该基因是前列腺癌的主要调节因子， 保护前列腺上皮免受与癌症相关的攻击的前列腺上皮特化 引发，包括氧化应激。我们的研究表明NKX3.1可以保护前列腺细胞 通过调节细胞核和线粒体中的基因表达来防止氧化应激。我们发现，在 NKX3.1除了在细胞核中作为转录因子的预期功能外，还定位于 线粒体对氧化应激的反应，在那里它调节线粒体编码的 控制活性氧（ROS）的基因。因此，我们假设NKX3.1调节氧化 通过其在细胞核和线粒体中的协调功能来应激，并且这些功能是必要的， 维持前列腺上皮分化并抑制癌症发生。由于相对较少的核 转录调节蛋白已被证明在线粒体中起作用，我们的研究提供了一个独特的 有机会了解组织特异性转录因子如何控制不同亚细胞中的氧化应激， 细胞区室，以及这些活动与癌症的相关性。 在目的1中，我们将研究NKX3.1在细胞核中保护免受氧化应激的功能 促进差异化。我们将研究：（i）NKX3.1的核转录调控功能 （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。在目标2中，我们将研究新的 NKX3.1在线粒体中的功能。根据我们的初步数据显示，在应对氧化 应激时，NKX3.1定位于线粒体，在那里它调节线粒体编码的 基因，我们将研究：（i）与NKX3.1定位到线粒体相关的机制;（ii） NKX3.1调节哺乳动物编码基因的机制，特别是与其 核基因的调控;以及（iii）NKX3.1的这些神经特异性功能对于 调节氧化应激和细胞分化。在目标3中，我们将补充这些机制 通过开展联合临床研究来评价NKX3.1调节氧化应激的相关性 用于抑制前列腺癌，以及这些活性是否可以用于癌症预防， 基因工程小鼠模型和人前列腺组织器官型模型。 PAR-17-203的相关性：我们提出的研究提供了一个独特的机会来阐明分子 控制氧化应激和分化与癌症发生之间平衡的机制，以及如何 这些在细胞核和线粒体之间协调。