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

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 通过我们对NKX3.1同源盒基因的研究，它是前列腺癌的主要调节基因 保护前列腺上皮免受癌症侵袭的前列腺上皮规范 启动，包括氧化应激。我们的研究发现，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 除了作为核内转录因子的预期功能外，NKX3.1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表达 控制活性氧(ROS)的基因。因此，我们假设NKX3.1调节氧化 应激通过其在细胞核和线粒体中的协调功能，以及这些功能是必要的 维持前列腺上皮细胞分化，抑制癌变。由于相对较少的核能 转录调节蛋白已被证明在线粒体中发挥功能，我们的研究提供了一种独特的 有机会了解组织特异性转录因子如何控制不同亚型的氧化应激 以及这些活动与癌症的相关性。 在目标1中，我们将研究NKX3.1在细胞核中保护氧化应激的功能 和促进差异化。我们将研究：(I)NKX3.1的核转录调控功能 用于防止氧化应激；(Ii)它们与前列腺上皮分化和癌症的相关性；以及 (Iii)这些功能是否影响线粒体功能，如果影响，又如何影响线粒体功能。在目标2中，我们将调查小说 NKX3.1在线粒体中的功能。根据我们的初步数据显示，在对氧化的反应 应激，NKX3.1定位于线粒体，在那里它调节线粒体编码的表达 基因，我们将研究：(I)NKX3.1定位于线粒体的相关机制；(Ii) NKX3.1调控线粒体编码基因的机制，特别是与其 核基因的调控；以及(Iii)NKX3.1的这些线粒体特异性功能对 氧化应激和细胞分化的调节。在目标3中，我们将补充这些机制 通过实施联合临床研究来评估NKX3.1对氧化应激调节的相关性 用于抑制前列腺癌，以及这些活动是否可以被用于癌症预防 基因工程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启动之间平衡的机制和方式 这些是在细胞核和线粒体之间协调的。

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.