Nrf2 通过抑制 Krüppel 样因子 9（KLF9）的活性来调节的表达。

Nrf2 Regulates the Expression of by Inhibiting the Activity of Krüppel-Like Factor 9 (KLF9).

机构信息

Department of Chemistry and Biochemistry, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia.

Department of Biomedical Chemistry, School of Biological and Environmental Sciences, Kwansei Gakuin University, Sanda, Japan.

出版信息

Curr Drug Metab. 2023;24(9):667-681. doi: 10.2174/0113892002271342231013095255.

DOI:10.2174/0113892002271342231013095255

PMID:37916628

Abstract

AIMS

The aim of the present study is to gain insight into the biology of Parkinson's disease (PD) and cancer to drive translational advances enabling more effective prevention and/or potential treatments.

BACKGROUND

The expression of Cytochrome P450 2D6 (CYP2D6) is correlated with various diseases such as PD and cancer; therefore, exploring its regulatory mechanism at transcriptional levels is of interest. NF-E2-related factor 2 (Nrf2) has been known to be responsible for regulating phase II and phase III drug-metabolizing genes.

OBJECTIVES

The objectives of this study are to investigate the transcriptional regulation of by Nrf2 and to analyze its role in PD and cancer.

METHODS

Nrf2 was transiently expressed in human hepatoma Hep3B cells, and the expression of was examined by RT-qPCR. The promoter activity of and the DNA binding of Nrf2 were examined by luciferase and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.

RESULTS

In the present study, we demonstrated that Nrf2 down-regulated mRNA expression in hepatoma Hep3B cells. Mechanistically, Nrf2 binds to the antioxidant responsive element (ARE) in the proximity of krüppel- like factor 9 (KLF9)-binding site within the -550/+51 of promoter. The inhibition and activation of Nrf2 enhanced and suppressed KLF9 effects on expression, respectively. The expression levels of Nrf2 and were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control tissues, and Nrf2 was negatively correlated with . In liver cancer patients, decreased levels were apparent and associated with a lower probability of survival.

CONCLUSION

Our work revealed the inhibitory role of Nrf2 in regulating expression. Moreover, Nrf2- dependent regulation of can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.

摘要

目的

本研究旨在深入了解帕金森病（PD）和癌症的生物学特性，推动转化研究进展，以实现更有效的预防和/或潜在治疗。

背景

细胞色素 P450 2D6（CYP2D6）的表达与 PD 和癌症等多种疾病相关，因此，探索其转录水平的调控机制具有重要意义。NF-E2 相关因子 2（Nrf2）已被证实负责调节Ⅱ相和Ⅲ相药物代谢基因。

目的

本研究旨在探讨 Nrf2 对的转录调控及其在 PD 和癌症中的作用。

方法

瞬时转染 Nrf2 于人肝癌 Hep3B 细胞，采用 RT-qPCR 检测的表达。通过荧光素酶和 ChIP 实验分别检测的启动子活性和 Nrf2 的 DNA 结合。随后，我们在基因表达综合数据库（GEO）和癌症基因组图谱（TCGA）数据库中研究了 Nrf2 和在 PD 和癌症中的表达和相关性。

结果

本研究表明，Nrf2 可下调 Hep3B 细胞中的 mRNA 表达。机制上，Nrf2 结合于启动子 -550/+51 区域内的 Krüppel 样因子 9（KLF9）结合位点附近的抗氧化反应元件（ARE）。Nrf2 的抑制和激活分别增强和抑制了 KLF9 对表达的影响。与健康对照组组织相比，PD 患者 GEO 数据集的 Nrf2 和表达水平上调，且 Nrf2 与呈负相关。在肝癌患者中，水平降低，且与生存率降低相关。