Requirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA-induced mouse skin cell transformation by sulforaphane.
Level 5 - mechanism / opinion, no new human data
In vitro bench research using a mouse epidermal cell line.
PubMed 24441674 · doi:10.1158/1940-6207.CAPR-13-0313-T
What was done
Investigators evaluated whether sulforaphane (SFN) inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transformation in mouse skin epidermal JB6 (JB6 P+) cells. They measured Nrf2 nuclear translocation, downstream target gene expression (HO-1, NQO1, UGT1A1), and transformation following Nrf2 knockdown. Epigenetic mechanisms were examined via bisulfite genomic sequencing of the first 15 CpGs of the Nrf2 promoter, DNA methyltransferase expression (DNMT1, DNMT3a, DNMT3b), total histone deacetylase (HDAC) activity, and HDAC isoform levels (HDAC1-4).
What was found
After 5 days of treatment, SFN significantly inhibited TPA-induced JB6 cell transformation, enhanced Nrf2 nuclear translocation, and increased HO-1, NQO1, and UGT1A1 mRNA and protein levels. Nrf2 knockdown attenuated induction of Nrf2, HO-1, and NQO1 and reduced SFN's protective effect against transformation. SFN decreased the methylation ratio of the first 15 CpGs in the Nrf2 promoter, reduced DNMT1, DNMT3a, and DNMT3b protein levels, inhibited total HDAC activity, and decreased HDAC1, HDAC2, HDAC3, and HDAC4 protein expression. Specific quantitative values were not provided in the abstract.
Why it matters
The study outlines an epigenetic mechanism whereby sulforaphane reactivates Nrf2 through promoter demethylation and histone modification, offering a molecular rationale for dietary chemoprevention against skin carcinogenesis.
Limits
The study was conducted entirely in vitro using a mouse cell line, without in vivo animal confirmation or human tissue validation. The abstract omits precise quantitative metrics, dose concentrations, sample replicates, and statistical confidence intervals.
Cited by
- supports Sulforaphane treatment upregulates RNA expression levels of Nrf2 and Keap1.