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2018 ; 52
(6
): 1899-1911
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Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation
#MMPMID29620187
Tang G
; Guo J
; Zhu Y
; Huang Z
; Liu T
; Cai J
; Yu L
; Wang Z
Int J Oncol
2018[Jun]; 52
(6
): 1899-1911
PMID29620187
show ga
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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