Title:Nrf2 Regulates the Expression of CYP2D6 by Inhibiting the Activity of Krüppel-Like
Factor 9 (KLF9)
Volume: 24
Issue: 9
Author(s): Ferbian Milas Siswanto*, Maria Dara Novi Handayani, Rita Dewi Firmasyah, Ami Oguro and Susumu Imaoka*
Affiliation:
- 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
- Department of Biomedical Chemistry, School of Biological and Environmental Sciences, Kwansei Gakuin University,
Sanda, Japan
Keywords:
Nrf2, CYP2D6, KLF9, transcriptional regulation, Parkinson’s disease, liver cancer.
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 CYP2D6 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 CYP2D6 was
examined by RT-qPCR. The promoter activity of CYP2D6 and the DNA binding of Nrf2 were examined by luciferase
and ChIP assay, respectively. We then investigated the expression and correlation of Nrf2 and CYP2D6 in
the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets.
Results: In the present study, we demonstrated that Nrf2 down-regulated CYP2D6 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 CYP2D6 promoter. The inhibition and activation of
Nrf2 enhanced and suppressed KLF9 effects on CYP2D6 expression, respectively. The expression levels of Nrf2
and CYP2D6 were upregulated and downregulated in the PD patient GEO datasets compared to the healthy control
tissues, and Nrf2 was negatively correlated with CYP2D6. In liver cancer patients, decreased CYP2D6 levels
were apparent and associated with a lower probability of survival.
Conclusion: Our work revealed the inhibitory role of Nrf2 in regulating CYP2D6 expression. Moreover, Nrf2-
dependent regulation of CYP2D6 can be used as a prognostic factor and therapeutic strategy in PD and liver cancer.