Apigenin Reactivates Nrf2 Anti-oxidative Stress Signaling in Mouse Skin Epidermal JB6 P + Cells Through Epigenetics Modifications

Journal Title: The AAPS Journal - Year 2014, Vol 16, Issue 4

Abstract

Nrf2 is a crucial transcription factor that controls a critical anti-oxidative stress defense system and is implicated in skin homeostasis. Apigenin (API), a potent cancer chemopreventive agent, protects against skin carcinogenesis and elicits multiple molecular signaling pathways. However, the potential epigenetic effect of API in skin cancer chemoprotection is not known. In this study, bisulfite genomic DNA sequencing and methylated DNA immunoprecipitation were utilized to investigate the demethylation effect of API at 15 CpG sites in the Nrf2 promoter in mouse skin epidermal JB6 P + cells. In addition, qPCR and Western blot analyses were performed to evaluate the mRNA and protein expression of Nrf2 and the Nrf2 ARE downstream gene, NQO1. Finally, the protein expression levels of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) were evaluated using API and the DNMT/HDAC inhibitor 5-aza/ trichostatin A. Our results showed that API effectively reversed the hypermethylated status of the 15 CpG sites in the Nrf2 promoter in a dose-dependent manner. API enhanced the nuclear translocation of Nrf2 and increased the mRNA and protein expression of Nrf2 and the Nrf2 downstream target gene, NQO1. Furthermore, API reduced the expression of the DNMT1, DNMT3a, and DNMT3b epigenetic proteins as well as the expression of some HDACs (1–8). Taken together, our results showed that API can restore the silenced status of Nrf2 in skin epidermal JB6 P + cells by CpG demethylation coupled with attenuated DNMT and HDAC activity. These results may provide new therapeutic insights into the prevention of skin cancer by dietary phytochemicals.

Authors and Affiliations

Ximena Paredes-Gonzalez, Francisco Fuentes, Zheng-Yuan Su, Ah-Ng Tony Kong

Keywords

Related Articles

Organic Cation Transporter OCTs (SLC22) and MATEs (SLC47) in the Human Kidney

In the kidney, human organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are the major transporters for the secretion of cationic drugs into the urine. In the human kidney, OCT2 mediates...

Pharmacokinetic mAb–mAb Interaction: Anti-VEGF mAb Decreases the Distribution of Anti-CEA mAb into Colorectal Tumor Xenografts

To date, there has been little investigation of the risk for drug–drug interactions involving monoclonal antibodies. The present work examined the effects of an anti-vascular endothelial growth factor (anti-VEGF)...

CYP2D6 Genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting

The emerging application of pharmacogenomics in the clinical trial setting requires careful comparison with more traditional phenotyping methodologies, particularly in the drug metabolism area where phenotyping is used e...

Performance of Three Estimation Methods in Repeated Time-to-Event Modeling

It is not uncommon that the outcome measurements, symptoms or side effects, of a clinical trial belong to the family of event type data, e.g., bleeding episodes or emesis events. Event data is often low in information co...

PTD-mediated Loading of Tumor-Seeking Lymphocytes with Prodrug-Activating Enzymes

Using the approach of peptide transduction domain (PTD)-mediated loading of interleukin-2(IL-2)-activated natural killer (A-NK) cells, tumor-seeking lymphocytes, with prodrug-activating enzymes, we primarily aim to gener...

Download PDF file
  • EP ID EP681701
  • DOI  10.1208/s12248-014-9613-8
  • Views 81
  • Downloads 0

How To Cite

Ximena Paredes-Gonzalez, Francisco Fuentes, Zheng-Yuan Su, Ah-Ng Tony Kong (2014). Apigenin Reactivates Nrf2 Anti-oxidative Stress Signaling in Mouse Skin Epidermal JB6 P + Cells Through Epigenetics Modifications. The AAPS Journal, 16(4), -. https://europub.co.uk/articles/-A-681701