Related Experiment Video
Updated: Feb 17, 2026
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1
Wenji Li, Zheng-Yuan Su1, Yue Guo
1Department of Bioscience Technology, Chung Yuan Christian University , 200 Chung Pei Road, Chung Li District, Taoyuan City, Taiwan 32023, R.O.C.
Abstract:
The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-bis-(3,4,5-trimethoxybenzylidene)-tetrahydro-thiopyran-4-one (F10) and (3E,5E)-3,5-bis-(3,4,5-trimethoxy-benzylidene)-tetrahydropyran-4-one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin, and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways. We performed real-time quantitative PCR and Western blotting to investigate the effects of F10 and E10 on Nrf2, correlated phase II detoxification genes. We also measured expression and activity of DNMTand HDAC enzymes. Enrichment of H3K27me3 on the promoter region of Nrf2 was explored with a chromatin immunoprecipitation (ChIP) assay. Methylation of the CpG region in Nrf2 promoter was doubly examined by bisulfite genomic sequencing (BGS) and methylation DNA immunoprecipitation (MeDIP). Compared with curcumin and SFN, F10 is more potent in activating Nrf2-ARE pathways. Both F10 and E10 enhanced level of Nrf2 and the correlated phase II detoxifying genes. BGS and MeDIP assays indicated that F10 but not E10 hypomethylated the Nrf2 promoter. F10 also downregulated the protein level of DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC4, and HDAC7 and the activity of DNMTs and HDACs. F10 but not E10 effectively reduced the accumulation of H3k27me3 on the promoter of Nrf2. F10 and E10 can activate the Nrf2-ARE pathway and increase the level of Nrf2 and correlated phase II detoxification genes. The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation.
Insights
Synthetic curcumin derivatives F10 and E10 activate the Nrf2-ARE pathway, restoring Nrf2 activity and detoxifying genes in prostate cancer models. F10 shows superior potency by demethylating the Nrf2 promoter and reducing epigenetic modifiers.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- Prostate cancer (PCa) carcinogenesis in TRAMP models correlates with Nrf2 promoter hypermethylation and reduced Nrf2 transcription.
- Nrf2 regulates detoxifying genes crucial for cellular defense against carcinogens.
Purpose of the Study:
- To investigate the effects of synthetic curcumin derivatives, F10 and E10, on restoring Nrf2 activity in TRAMP C1 cells.
- To compare the potency of F10 and E10 in activating the Nrf2-ARE pathway against curcumin and sulforaphane (SFN).
Main Methods:
- Real-time quantitative PCR and Western blotting to assess Nrf2 and phase II detoxifying gene expression.
- Chromatin immunoprecipitation (ChIP), bisulfite genomic sequencing (BGS), and methylation DNA immunoprecipitation (MeDIP) to analyze Nrf2 promoter methylation and epigenetic modifications.
- Assays to measure DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme expression and activity.
Main Results:
- F10 demonstrated greater potency than curcumin and SFN in activating the Nrf2-ARE pathway.
- Both F10 and E10 enhanced Nrf2 levels and associated phase II detoxifying genes.
- F10, but not E10, hypomethylated the Nrf2 promoter, downregulated DNMTs and HDACs, and reduced H3K27me3 enrichment on the Nrf2 promoter.
Conclusions:
- F10 and E10 effectively activate the Nrf2-ARE pathway and upregulate Nrf2 and its target genes.
- F10's reactivation of Nrf2 in TRAMP C1 cells is attributed to demethylation, reduced HDACs, and inhibited H3K27me3 accumulation.
- These findings highlight F10 and E10 as potential therapeutic agents for prostate cancer by modulating epigenetic regulation of Nrf2.
