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Published on: December 26, 2016
Sirt2 suppresses glioma cell growth through targeting NF-κB-miR-21 axis
Ya'nan Li1, Dongwei Dai, Qiong Lu
1Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
Abstract:
Sirtuins are NAD(+)-dependent deacetylases that regulate numerous cellular processes including aging, DNA repair, cell cycle, metabolism, and survival under stress conditions. The roles of sirtuin family members are widely studied in carcinogenesis. However, their roles in glioma remain unclear. Here we report that Sir2 was under expressed in human glioma tissues and cell lines. We found that Sirt2 overexpression decreased cell proliferation and colony formation capacity. In addition, Sirt2 overexpression induced cellular apoptosis via up-regulating cleaved caspase 3 and Bax, and down-regulating anti-apoptotic protein Bcl-2. Sirt2 knockdown obtained opposing results. We showed that Sirt2 overexpression inhibited miR-21 expression, and Sirt2 was not sufficient to reduce cell proliferation and colony formation as well as to induce apoptosis when miR-21 was knocked down in glioma cells. Mechanically, we demonstrated that Sirt2 deacetylated p65 at K310 and blocked p65 binding to the promoter region of miR-21, thus regressing the transcription of miR-21. In summary, Sirt2 is critical in human glioma via NF-κB-miR-21 pathway and Sirt2 activator may serve as candidate drug for glioma therapy.
Insights
Sirtuin 2 (Sir2) is underexpressed in glioma. Overexpressing Sir2 inhibits glioma cell growth and induces apoptosis by suppressing miR-21 via the NF-κB pathway, suggesting Sir2 activators as potential glioma therapeutics.
Area of Science:
- Molecular Biology
- Oncology
- Cellular Biology
Background:
- Sirtuins (NAD(+)-dependent deacetylases) are involved in various cellular processes, including aging and cancer.
- The specific roles of sirtuins, particularly Sirtuin 2 (Sir2), in glioma pathogenesis are not well understood.
Purpose of the Study:
- To investigate the role of Sirtuin 2 (Sir2) in human glioma.
- To elucidate the molecular mechanisms underlying Sir2's function in glioma, focusing on its interaction with microRNA-21 (miR-21).
Main Methods:
- Analysis of Sir2 expression in human glioma tissues and cell lines.
- Overexpression and knockdown studies of Sir2 in glioma cells.
- Assessment of cell proliferation, colony formation, and apoptosis.
- Investigation of miR-21 expression levels and its regulation by Sir2.
- Mechanistic studies involving p65 acetylation and its effect on miR-21 transcription.
Main Results:
- Sir2 was found to be underexpressed in human glioma tissues and cell lines.
- Overexpression of Sir2 suppressed glioma cell proliferation and colony formation, while inducing apoptosis.
- Sir2 overexpression inhibited miR-21 expression, and this inhibition was crucial for Sir2's anti-glioma effects.
- Mechanistically, Sir2 deacetylated p65 at K310, preventing p65 binding to the miR-21 promoter and thus repressing miR-21 transcription.
Conclusions:
- Sirtuin 2 plays a critical tumor-suppressive role in human glioma through the NF-κB-miR-21 pathway.
- Sirt2 activators represent a promising therapeutic strategy for glioma treatment.
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