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

Jia Bao Yan, Chien Cheng Lai, Jin Wei Jhu, Brendan Gongol, Traci L. Marin, Shih Chieh Lin, Hsiang Yi Chiu, Chia Jui Yen, Liang Yi Wang, I. Chen Peng

Research output: Contribution to journalArticlepeer-review

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. Peng and colleagues demonstrate that c-Myc activates, whereas AMP-activated protein kinase (AMPK) inhibits, thymine DNA glycosylase (TDG)-mediated DNA demethylation of the sterol regulatory element-binding protein 1 (SREBP1) promoter in insulin-promoted and metformin-suppressed cancer progression, respectively. Therefore, targeting TDG represents an epigenetic-based therapeutic strategy for cancers associated with type 2 diabetes mellitus.

Original languageEnglish
Pages (from-to)282-294
Number of pages13
JournalMolecular Therapy - Oncolytics
Volume18
DOIs
Publication statusPublished - 2020 Sep 25

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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