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Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage

Authors Wang Y, Guo Y, Gao J, Yuan X

Received 27 April 2018

Accepted for publication 30 June 2018

Published 9 November 2018 Volume 2018:10 Pages 5591—5603

DOI https://doi.org/10.2147/CMAR.S172509

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Justinn Cochran

Peer reviewer comments 3

Editor who approved publication: Professor Nakshatri


Yumei Wang,1 Yinmou Guo,2 Jianzhi Gao,3 Xiangdong Yuan1

1Department of Children’s Rehabilitation, Shangqiu First People’s Hospital of Henan, Shangqiu, Henan, China; 2First Department of Oncology, Shangqiu First People’s Hospital of Henan, Shangqiu, Henan, China; 3Department of Oncology, Zhuozhou Hospital of Beijing 301 Hospital, Beijing, China

Background: SIRT4 is a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent enzymes located in the mitochondria, and is involved in regulating energy metabolism, stress response, and cellular lifespan in mammalian cells. However, its function in human neuroblastoma (NB) remains unexplored.
Methods: Expression of SIRT4 in 158 pairs of human NB tumor tissues and adjacent normal tissues collected from March 2009 to October 2012 was analyzed by immunohistochemistry, Western blotting, and real-time fluorescence quantitative PCR. For in vitro study, SIRT4 was overexpressed in SH-SY5Y, SK-N-BE, and IMR-32 cells to study the effects of SIRT4 expression on proliferation, invasion, and migration of human NB cells and on mitochondrial function.
Results: SIRT4 gene expression in human NB tumor tissues was significantly lower than that in adjacent normal tissues (P<0.001). SIRT4 expression was lower in NB patients with higher International Neuroblastoma Staging System stage (P=0.018), with lymph node metastasis, than patients without lymph node metastasis (P<0.001). Survival times of NB patients with low expression of SIRT4 were significantly shorter than those of patients with high expression of SIRT4 (P=0.0036). Overexpression of SIRT4 significantly reduced the proliferation, invasion, and migration ability of NB cells as well as mitochondrial energy production, and caused SIRT1 upregulation and mitochondrial damage in NB cells.
Conclusion: SIRT4 exhibits a tumor suppressor function in human NB and inhibits mitochondrial metabolism and SIRT1 expression in tumor cells, thereby reducing the energy metabolism of tumor cells. These results suggest that SIRT4 may be a new therapeutic target for human NB.

Keywords: neuroblastoma, SIRT4, energy metabolism, SIRT1

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