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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：
10058251
负责人：
Cory Abate-Shen
金额：
$ 38.71万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10058251
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/antagonist 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.

项目总结/文摘