Metformin Affects Cancer Regulation and Metabolism of Oral Squamous Cell Carcinoma Partially Through Upregulation of H3K27ac 

Abstract Objectives Metformin, a first-line drug that has been used for type 2 diabetes treatment, recently attracts broad attention for its therapeutic effects on diverse human cancers. However, its effect and underlying mechanisms in oral squamous cell carcinoma (OSCC) are not well known. Materials and Methods OSCC cells were used to detect the effect of metformin on cell proliferation, colony formation, cell cycle and migration in vitro. Tumor growth of nude mice was conducted to detect the effect of metformin in vivo. Western blotting and immunohistochemistry were used to investigate the effect of metformin on the expression of histone modification in vitro and vivo. The combined effect on cell proliferation and histone modification of metformin and downregulation of EZH2 was detected by CCK8 and western blotting. Additionally, RNA-seq and ChIP-seq was performed to explore the underlying mechanisms of metformin in OSCC.Results Metformin could inhibit OSCC cell proliferation and tumor growth with the increased acetylation at lysine 27 of histone H3 (H3K27ac) in vitro and vivo. The underlying mechanisms were related to cancer regulation and cancer metabolism, affected by the increased H3K27ac. Additionally, metformin could synergize with siRNA-EZH2 to inhibit OSCC cell proliferation independent on the increased H3K27ac.Conclusions Metformin could play anti-cancer role in OSCC progression, with the reprogramming of cancer regulation and metabolism partially regulated by the increased H3K27ac.