TY - JOUR
T1 - Insulin and Metformin Control Cell Proliferation by Regulating TDG-Mediated DNA Demethylation in Liver and Breast Cancer Cells
AU - Yan, Jia Bao
AU - Lai, Chien Cheng
AU - Jhu, Jin Wei
AU - Gongol, Brendan
AU - Marin, Traci L.
AU - Lin, Shih Chieh
AU - Chiu, Hsiang Yi
AU - Yen, Chia Jui
AU - Wang, Liang Yi
AU - Peng, I. Chen
N1 - Funding Information:
We thank Drs. Wei-Xing Zong, Etienne Lefei, Michael Hsiao, Hung-Jiun Liaw, Hao-Ven Wang, Wen-Tai Chiu, Yau-Sheng Tsai, Horng-Yih Ou, Yun-Wen Chen, and Shun-Fen Tzeng for sharing plasmids, cell lines, and reagents. We thank Drs. Wei-Xing Zong and Richard Lin for reading and discussion. We also thank Miss Huan-Tzu Hou for drawing diagrams. This work was supported by grants from the Ministry of Science and Technology, Taiwan (MOST 104-2320-B-006-006, MOST 104-2320-B-006-031, and MOST 105-2628-B-006-005-MY3 to I.-C.P.), and the Headquarters of University Advancement at the National Cheng Kung University, sponsored by the Ministry of Education, Taiwan, to I.-C.P.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/9/25
Y1 - 2020/9/25
N2 - 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.
AB - 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.
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U2 - 10.1016/j.omto.2020.06.010
DO - 10.1016/j.omto.2020.06.010
M3 - Article
AN - SCOPUS:85088091476
SN - 2372-7705
VL - 18
SP - 282
EP - 294
JO - Molecular Therapy - Oncolytics
JF - Molecular Therapy - Oncolytics
ER -