Background
Glioma is a highly malignant primary nervous system tumor. Temozolomide(TMZ) is a commonly used chemotherapy drug, but drug resistance is increasing. Therefore, finding effective biomarkers can help us to better stratify and individualize treatment. Sirt7 is the latest member of sirtuins, which mainly plays the role of NAD+-dependent histone deacetylase. In recent years, Sirt7 has been reported to be related to the proliferation and oncogenic activity of malignant tumors such as melanoma and colon cancer, but it has been less reported in glioma. This study aimed to explore the role of Sirt7 in glioma by determining its effects on glioma cell proliferation, apoptosis, and cell cycle progression; whether Sirt7 knockdown increases the cytotoxicity of TMZ; and the regulatory microRNAs (miRNAs) upstream of Sirt7.
Methods
We found that Sirt7 expression was significantly upregulated in glioma tissues and cells and was correlated with tumor grade and patient Survival. We constructed Sirt7 overexpression and knockdown lentivirus for the infection of U87, U251, and LN229 cells, Expression levels of Sirt7 and miR-148a-3p were evaluated by RT-qPCR and western blotting. Cell proliferation was measured using the CCK-8 assay. Cell cycle progression and apoptosis were assessed using flow cytometry. We verified the effect of changes in Sirt7 expression on the cytotoxic effects of TMZ on glioma. Dual luciferase gene reporter assays were used to investigate the targeted regulation of Sirt7 by miR-148a-3p. The effect of SIRT7 on TMZ toxicity in glioma tumorigenesis were assessed using mouse xenotransplantation.
Results
Sirt7 expression was positively correlated with the pathological grade of glioma patients and negatively correlated with patient survival. Both knockdown and overexpression of Sirt7 affected the proliferation, apoptosis, and cell cycle progression in glioma cells and enhanced TMZ-induced cytotoxicity. Sirt7 is a target of miR-148a-3p, and miR-148a-3p expression in glioma tissues and cells was significantly decreased. In xenograft models, knockdown of Sirt7 inhibited tumor growth and enhanced TMZ-mediated antitumor effects.
Conclusion
This study deepens our understanding of the molecular functions of Sirt7, provides evidence that Sirt7 enhances TMZ-induced cytotoxicity in glioma, and demonstrates the potential of Sirt7 as a therapeutic target.