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DNA Methylome and Transcriptome Study of Triterpenoid CDDO in TPA-Mediated Skin Carcinogenesis Model

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Abstract

Overexposure to ultraviolet radiation and environmental carcinogens drive skin cancer development through redox imbalance and gene mutation. Antioxidants such as triterpenoids have exhibited anti-oxidative and anti-inflammatory potentials to alleviate skin carcinogenesis. This study investigated the methylome and transcriptome altered by tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) or TPA with 2-cyano 2,3-dioxoolean-1,9-dien-28-oic acid (CDDO). The results show that CDDO blocks TPA-induced transformation dose dependently. Several differential expressed genes (DEGs) involved in skin cell transformation, while counteracted by CDDO, were revealed by differential expression analysis including Lyl1, Lad1, and Dennd2d. In CpG methylomic profiles, the differentially methylated regions (DMRs) in the promoter region altered by TPA while showing the opposite methylation status in the CDDO treatment group were identified. The correlation between DNA methylation and RNA expression has been established and DMRs showing inverse correlation were further studied as potential therapeutic targets. From the CpG methylome and transcriptome results, CDDO significantly restored gene expression of NAD(P)H:quinone oxidoreductase 1 (Nqo1) inhibited by TPA by decreasing their promoter CpG methylation. Ingenuity Pathways Analysis (IPA) shows that CDDO neutralized the effect of TPA through modulating cell cycles, cell migration, and inflammatory and immune response regulatory pathways. Notably, Tumor Necrosis Factor Receptor 2 (TNFR2) signaling was significantly downregulated by CDDO potentially contributing to prevention of TPA-induced cell transformation. Overall, incorporating the transcriptome, CpG methylome, and signaling pathway network, we reveal potential therapeutic targets and pathways by which CDDO could reverse TPA-induced carcinogenesis. The results could be useful for future human study and targets development for skin cancer.

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Acknowledgements

This paper is dedicated to Professor Michael B. Sporn, the discoverer of CDDO series of triterpenoids, making great contribution to cancer chemoprevention research, who passed away recently. In addition, the authors are thankful to Lujing Wang in Dr. Kong’s laboratory for providing helpful insight into the study design, data analyses, and manuscript writing. The graphical abstract was created with BioRender.com.

Funding

This work is supported in part by institutional funds, R01 CA200129, from the National Cancer Institute and AT009152 from the National Center for Complementary and Integrative Health (NCCIH) to A-NTK.

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  1. Department 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

    Hsiao-Chen Dina Kuo, Renyi Wu, Md. Shahid Sarwar, Chao Wang, Davit Sargsyan & Ah-Ng Tony Kong

  2. Graduate Program of Pharmaceutical Sciences, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, Piscataway, USA

    Hsiao-Chen Dina Kuo & Davit Sargsyan

  3. Department of Statistics and Biostatistics, Rutgers, The State University of New Jersey, NJ, 08854, Piscataway, USA

    Meinizi Zheng

  4. Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, NJ, Piscataway, USA

    Nanjoo Suh

  5. Rutgers Cancer Institute of New Jersey, NJ, New Brunswick, USA

    Nanjoo Suh

Authors
  1. Hsiao-Chen Dina Kuo
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  2. Renyi Wu
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  3. Md. Shahid Sarwar
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  4. Meinizi Zheng
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  5. Chao Wang
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  6. Davit Sargsyan
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  7. Nanjoo Suh
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  8. Ah-Ng Tony Kong
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Contributions

Participated in research design: H-CDK, A-NTK. Conducted experiments: H-CDK. Performed data analysis: H-CDK, RW, MZ, CW, DS. Wrote the manuscript: H-CDK, MSS. Reviewed the manuscript: A-NTK, NS, MSS, H-CDK.

Corresponding author

Correspondence to Ah-Ng Tony Kong.

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Conflict of Interest

NS is an inventor on patents dealing with chemical synthesis of triterpenoids and their application in cancer as well as inflammatory diseases. The rest of the authors declare no conflict of interest.

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Kuo, HC.D., Wu, R., Sarwar, M.S. et al. DNA Methylome and Transcriptome Study of Triterpenoid CDDO in TPA-Mediated Skin Carcinogenesis Model. AAPS J 24, 115 (2022). https://doi.org/10.1208/s12248-022-00763-5

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