Open Access

Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation

  • Authors:
    • Guiju Tang
    • Jianfeng Guo
    • Yapei Zhu
    • Zaiju Huang
    • Ting Liu
    • Jing Cai
    • Lili Yu
    • Zehua Wang
  • View Affiliations

  • Published online on: March 29, 2018     https://doi.org/10.3892/ijo.2018.4343
  • Pages: 1899-1911
  • Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Metformin has been used for the treatment of type II diabetes mellitus for decades. Recently, used of metformin in the therapy of diverse human cancer types has received widespread attention, while the underlying mechanisms have been not fully elucidated. In the current study, 5-ethynyl-20-deoxyuridine assay to detect cell proliferation, flow cytometry to detect apoptosis, scratch wound healing and Transwell migration assay to detect cell migration capacity. The current study reported that metformin inhibited cell proliferation and migration, and promoted apoptosis in ovarian cancer cells, particularly under normoglycemic conditions in vitro. Metformin treatment significantly promoted the phosphorylation of AMP-activated protein kinase (AMPK), and reduced histone H3 lysine 27 trimethylation (H3K27me3) and polycomb repressor complex 2 (PRC2) levels. Additionally, overexpression of EZH2 to increase H3K27me3 abrogated the effect of metformin on the cell proliferation, migration and apoptosis in SKOV3 and ES2 cells. Similar to metformin, another AMPK agonist, 2-deoxy-D-glucose, reduced the H3K27me3 level and PRC2 expression. In cells pretreated with Compound C, an AMPK inhibitor, metformin was not able to induce AMPK phosphorylation or reduce H3K27me3. Metformin-mediated AMPK activation and H3K27me3 inhibition were more robust in cells exposed to low glucose (5.5 mM) compared with those exposed to high glucose (25 mM). These findings implicate H3K27me3 repression mediated by AMPK phosphorylation in the antitumor effect of metformin in ovarian cancer, indicating that metformin alters epigenetic modifications by targeting PRC2 and supports the use of metformin in treatment of patients with epithelial ovarian cancer without diabetes.
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June-2018
Volume 52 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Tang G, Guo J, Zhu Y, Huang Z, Liu T, Cai J, Yu L and Wang Z: Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. Int J Oncol 52: 1899-1911, 2018
APA
Tang, G., Guo, J., Zhu, Y., Huang, Z., Liu, T., Cai, J. ... Wang, Z. (2018). Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. International Journal of Oncology, 52, 1899-1911. https://doi.org/10.3892/ijo.2018.4343
MLA
Tang, G., Guo, J., Zhu, Y., Huang, Z., Liu, T., Cai, J., Yu, L., Wang, Z."Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation". International Journal of Oncology 52.6 (2018): 1899-1911.
Chicago
Tang, G., Guo, J., Zhu, Y., Huang, Z., Liu, T., Cai, J., Yu, L., Wang, Z."Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation". International Journal of Oncology 52, no. 6 (2018): 1899-1911. https://doi.org/10.3892/ijo.2018.4343