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Published on: December 19, 2019
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DNA Methylome and Transcriptome Study of Triterpenoid CDDO in TPA-Mediated Skin Carcinogenesis Model
Hsiao-Chen Dina Kuo1,2, Renyi Wu1, Md Shahid Sarwar1
1Department of Pharmaceutics, Center for Phytochemical Epigenome Studies, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, NJ, 08854, Piscataway, USA.
The AAPS Journal
|November 3, 2022
Summary
This study shows the antioxidant CDDO reverses skin cancer development caused by TPA by altering gene expression and DNA methylation. CDDO offers potential therapeutic targets for skin cancer prevention.
Area of Science:
- Molecular Biology
- Epigenetics
- Cancer Research
Background:
- Skin cancer is driven by UV radiation and carcinogens, leading to redox imbalance and mutations.
- Antioxidants like triterpenoids show potential in mitigating skin carcinogenesis.
- 12-O-tetradecanoylphorbol-13-acetate (TPA) is a known tumor promoter in skin.
Purpose of the Study:
- To investigate the effects of CDDO on TPA-induced skin carcinogenesis at the methylome and transcriptome levels.
- To identify potential therapeutic targets and pathways for reversing TPA-induced skin cancer.
- To elucidate the mechanisms by which CDDO counteracts TPA's effects.
Main Methods:
- Differential gene expression analysis to identify key genes affected by TPA and CDDO.
- CpG methylomic profiling to identify differentially methylated regions (DMRs).
- Correlation analysis between DNA methylation and gene expression.
- Ingenuity Pathway Analysis (IPA) to understand affected signaling pathways.
Main Results:
- CDDO dose-dependently blocked TPA-induced skin cell transformation.
- Identified differentially expressed genes (DEGs) like Lyl1, Lad1, and Dennd2d, counteracted by CDDO.
- Discovered TPA-induced promoter CpG methylation changes reversed by CDDO, restoring Nqo1 expression.
- CDDO modulated cell cycle, migration, and inflammatory/immune pathways, downregulating TNFR2 signaling.
Conclusions:
- CDDO effectively reverses TPA-induced epigenetic and transcriptomic alterations in skin carcinogenesis.
- CDDO restores normal gene expression by decreasing promoter CpG methylation, notably for Nqo1.
- CDDO's modulation of key cellular pathways, including TNFR2 signaling, highlights its therapeutic potential for skin cancer.
