Metformin inhibits histone H2B monoubiquitination and downstream gene transcription in human breast cancer cells

Abstract

Metformin, one of the most widely prescribed antihyperglycemic drugs, has recently received increasing attention for its potential effects with regard to cancer prevention and treatment. However, the mechanisms behind the suppression of cancer cell growth by metformin remain far from completely understood. The aim of the present study was to investigate whether metformin could regulate histone modification and its downstream gene transcription, and its potential function in inhibiting breast cancer cell proliferation. A T47D cell proliferation curve was determined by cell counting following metformin treatment with differing doses or time courses. The cell cycle was analyzed by flow cytometry with propidium iodide staining. Histone H2B monoubiquitination was evaluated by western blotting subsequent to histone extraction. The histone H2B monoubiquitination downstream gene expression level was determined by quantitative PCR. The results showed that metformin changed the cell-cycle check-point and inhibited breast cancer cell proliferation in a dose-dependent manner. AMPK was activated and histone H2B monoubiquitination and downstream gene transcription were inhibited following metformin treatment in the T47D cells. The effect of metformin on T47D cell proliferation was dependent on AMPK activity. It was concluded that metformin can suppress breast cancer cell growth by the activation of AMPK and the inhibition of histone H2B monoubiquitination and downstream gene transcription. This study reveals a novel potential mechanism of cancer cell growth suppression by metformin.

Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells

“…The reduction of ATP synthesis activates AMPK, and activated AMPK inhibits hepatic gluconeogenesis while stimulating muscular glucose uptake [ 29 ]. Many studies have found that metformin inhibits cell proliferation via unique mechanisms in different types of cancer cells [ 3 4 5 6 7 ]. However, the association between metformin (or AMPK) and hepatocellular carcinoma has not yet been elucidated.…”

“…A number of epidemiological and preclinical studies have suggested various mechanisms underlying the anticancer activity of metformin in different cancer types [ 3 ]. Previous studies have found diverse anticancer effects of metformin in human lung cancer cells [ 4 ], gastric cancer cells [ 5 ], endometrial cancer cells [ 6 ], breast cancer cells [ 7 ], and other types of cancer cells. These studies suggest that metformin inhibits cell proliferation by unique mechanisms in different types of cancer cells.…”

The association between glucose-lowering drug use and mortality among breast cancer patients with type 2 diabetes

“…Several laboratory studies show that metformin use is associated with cell growth suppression in breast cancer cells, possibly mediated by activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) [5,6]. Observational studies also show that metformin use is associated with a 20-30% lower breast cancer incidence [7][8][9].…”

Epigenetic effects of metformin: From molecular mechanisms to clinical implications

“…As O‐GlcNAcylation is thought to promote histone ubiquitination, they also found reduced ubiquitination at H2BK120. Although this study used a different AMPK activator, metformin has been proven to decrease H2BK120 ubiquitination in breast cancer cells . These studies both associated ubiquitination and O‐GlcNAcylation with increased gene expression, although both modifications have also been associated with gene silencing and linked to a variety of other histone modifications that may alter chromatin structure …”