Metformin Suppresses Hypopharyngeal Cancer Growth by Epigenetically Silencing Long Non-coding RNA SNHG7 in FaDu Cells

Local recurrence after therapy remains a challenging problem for hypopharyngeal cancer due to the chemotherapy resistance. Metformin has been linked to reduced cancer risk and better diagnosis through promoting global DNA methylation in cancer cells by controlling S-adenosylhomocysteine (SAHH) activity. However, the mechanisms by which metformin inhibits hypopharyngeal cancer remain elusive. In this study, we aim to investigate the role of metformin in hypopharyngeal cancer and illustrate the mechanism by which metformin regulates long non-coding RNAs (lncRNAs) expression. CCK-8 and annexin-V/PI double staining were performed to analyze the cell viability and apoptosis. LncRNA microarray analysis, QPCR, methylation specific PCR, western blot and RNA Immunoprecipitation were performed to analyze the molecular mechanism, Here, we report that metformin inhibits hypopharyngeal cancer cell proliferation in time- and dose-dependent manner by suppressing lncRNA SNHG7. Further investigations revealed that SNHG7 interacted with SAHH and metformin decreased SNHG7 expression by activating SAHH activity. Increased SAHH activity resulted in upregulating DNMT1 expression, leading to hypermethylation of SNHG7 promotor. In addition, upregulation of SNHG7 was associated with tumor size, differentiation, lymph node metastasis, distant metastasis and TNM stage. The patients with high SNHG7 have lower overall survival than that of with low SNHG7. Interestingly, SNHG7 levels were higher in taxol resistant patients than in taxol sensitive patients. Metformin sensitizes hypopharyngeal cancer to taxol through decreasing SNHG7. In conclusion, our recent study demonstrate that metformin is able to inhibit cancer cell proliferation by altering SNHG7 expression via SAHH-mediated DNA methylation. These findings also indicate that combined metformin with paclitaxel would be a novel therapeutic strategy to overcome resistance and prevent recurrence in hypopharyngeal cancer.