Insulin and Metformin Control Cell Proliferation by Regulating TDG-Mediated DNA Demethylation in Liver and Breast Cancer Cells

  • Mol Ther Oncolytics. 2020 Jun 24;18:282-294. doi: 10.1016/j.omto.2020.06.010.
Jia-Bao Yan  1 ,  Chien-Cheng Lai  1 ,  Jin-Wei Jhu  1 ,  Brendan Gongol  2 ,  Traci L Marin  3 ,  Shih-Chieh Lin  4 ,  Hsiang-Yi Chiu  1 ,  Chia-Jui Yen  5 ,  Liang-Yi Wang  6 ,  I-Chen Peng  1
Affiliations
  • 1. Department of Life Sciences, National Cheng Kung University, Tainan City 701, Taiwan.
  • 2. Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA.
  • 3. Department of Health Sciences, Victor Valley College, Victorville, CA 92395, USA.
  • 4. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan.
  • 5. Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan.
  • 6. Department of Public Health, National Cheng Kung University, Tainan City 701, Taiwan.
PMID: 32728616 DOI: 10.1016/j.omto.2020.06.010
Abstract

Type 2 diabetes mellitus (T2DM) is a frequent comorbidity of Cancer. Hyperinsulinemia secondary to T2DM promotes Cancer progression, whereas antidiabetic agents, such as metformin, have Anticancer effects. However, the detailed mechanism for Insulin and metformin-regulated Cancer cell proliferation remains unclear. This study identified a mechanism by which Insulin upregulated the expression of c-Myc, sterol regulatory element-binding protein 1 (SREBP1), and acetyl-coenzyme A (CoA) carboxylase 1 (ACC1), which are important regulators of lipogenesis and cell proliferation. Thymine DNA glycosylase (TDG), a DNA demethylase, was transactivated by c-Myc upon Insulin treatment, thereby decreasing 5-carboxylcytosine (5caC) abundance in the SREBP1 promoter. On the Other hand, metformin-activated AMP-activated protein kinase (AMPK) increased DNA Methyltransferase 3A (DNMT3A) activity to increase 5-methylcytosine (5mC) abundance in the TDG promoter. This resulted in decreased TDG expression and enhanced 5caC abundance in the SREBP1 promoter. These findings demonstrate that c-Myc activates, whereas AMPK inhibits, TDG-mediated DNA demethylation of the SREBP1 promoter in insulin-promoted and metformin-suppressed Cancer progression, respectively. This study indicates that TDG is an epigenetic-based therapeutic target for cancers associated with T2DM.

Keywords
AMPK; DNA demethylation; SREBP1; TDG; c-Myc; cancer; diabetes; insulin; metformin.
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