J Cancer 2022; 13(6):1859-1870. doi:10.7150/jca.63234 This issue

Research Paper

Transcriptional and H3K27ac related genome profiles in oral squamous cell carcinoma cells treated with metformin

Shan Liu1, Congyu Shi1, Xiaoru Hou1*, Xudong Tian1#, Chunjie Li1, Xiangrui Ma2, Xiaoyi Wang1✉, Pan Gao3✉

1. State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
2. Department of Oral and Maxillofacial Surgery, Binzhou Medical University Hospital, Binzhou, China.
3. State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of General and Emergency Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
* Present address: Department of Cranio-Maxillofacial Trauma and Plastic Surgery, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
# Present address: Department of 0ral and Maxillofacial Surgery, Guizhou Medical University, Guizhou, China.

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Citation:
Liu S, Shi C, Hou X, Tian X, Li C, Ma X, Wang X, Gao P. Transcriptional and H3K27ac related genome profiles in oral squamous cell carcinoma cells treated with metformin. J Cancer 2022; 13(6):1859-1870. doi:10.7150/jca.63234. Available from https://www.jcancer.org/v13p1859.htm

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Abstract

Graphic 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 the underlying mechanisms on oral squamous cell carcinoma (OSCC) are not well known.

Materials and Methods: OSCC cells were used to evaluate the effect of metformin on cell proliferation and colony formation in vitro. Tumor formation assay in nude mice was conducted to assess the effect of metformin in vivo. Western blotting and immunohistochemistry stain were performed to investigate the effect of metformin on the expression of acetylation at lysine 27 of histone H3 (H3K27ac) and methylation at lysine 27 of histone H3 (H3K27me3) in vitro and in vivo. RNA-seq and ChIP-seq were performed to explore the genome profile to metformin treatment in OSCC cells.

Results: Metformin inhibited OSCC cell proliferation and colony formation in vitro, as well as OSCC growth in vivo. Metformin increased the global H3K27ac modification in vitro. Transcriptome analysis suggested that metformin mainly downregulated pluripotency stem cell pathway, development involved pathways and upregulated cytokine and inflammatory pathways. Additionally, H3K27ac was involved in transcription, DNA repair and replication in metformin-treated OSCC cells.

Conclusions: Metformin inhibits OSCC growth concomitant upregulated global level of H3K27ac in vitro. This study provides insights into the molecule and epigenome basis on application of metformin in OSCC treatment, and highlights the underlying mechanisms of reprogrammed cancer regulation and epigenetic histone modification.

Keywords: Metformin, oral squamous cell carcinoma, H3K27ac, H3K27me3, reprogrammed cancer regulation