Abstract
Local recurrence after therapy remains a challenging problem for hypopharyngeal cancer (HPC) due to the chemotherapy resistance. Metformin is associated with reduced cancer risk through promoting global DNA methylation in cancer cells by controlling S-adenosylhomocysteine (SAHH) activity. However, the mechanisms by which metformin inhibits HPC remain elusive. In this study, we aim to investigate the role of metformin in HPC 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 FaDu 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 advanced 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 FaDu cells to taxol and irradiation through decreasing SNHG7. In conclusion, our recent study demonstrates that metformin inhibits FaDu cell proliferation by decreasing SNHG7 expression via SAHH-mediated DNA methylation. These findings indicate that combined metformin with paclitaxel or irradiation would be a novel therapeutic strategy to overcome resistance and prevent recurrence in HPC.
Highlights
In early-staged hypopharyngeal cancer (HPC), the overall and disease-specific survival rates after organ-preserving adjuvant chemoradiotherapy is satisfied (Chen et al, 2013)
We further investigated whether the inhibitory roles of metformin in HPC through long non-coding RNAs (lncRNAs)
We confirmed the expression of lncRNA SNHG7, LINC01504, and LINC00189 by Quantitative polymerase chain reaction (qPCR) in cells after metformin treatment, and found that metformin reduced SNHG7 expression, but not LINC01504 and LINC00189, in a dose- and time-dependent manner (Figures 2B,C)
Summary
In early-staged hypopharyngeal cancer (HPC), the overall and disease-specific survival rates after organ-preserving adjuvant chemoradiotherapy is satisfied (Chen et al, 2013). HPC still remains one of the worst prognose cancers with high mortality (Chan and Wei, 2013). Chemoradiotherapy is the first line treatment for advanced HPC (Bradley and Bradley, 2012). A first-line drug for type 2 diabetes, is associated with reduced cancer risk. It was reported that metformin promoted global DNA methylation by decreasing S-adenosylhomocysteine (SAHH) (Cuyas et al, 2018). DNA methylation may induce dysregulated gene expression. Metformin treatment could reduce the levels of histone methyltransferase of H3 Lys (SUV39H1) to inhibit migration of prostate cancer cells (Yu et al, 2017). The mechanisms by which metformin inhibits HPC remain elusive
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