SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway

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Abstract

SIRT4 is well-known for its deacetylase activity in energy metabolism, but little is known about its roles in carcinogenesis. We demonstrated that SIRT4 was decreased in 70 out of 133 non-small cell lung cancer (NSCLC) cases by immunohistochemical staining and localized in the mitochondria using confocal microscopy. Low levels of SIRT4 expression was correlated with tumor node metastasis (TNM) stage, histological type of tumor (adenocarcinoma), lymph nodal status, Ki-67 (proliferation index) and poor overall survival. We also studied the biological role of SIRT4 in lung cancer cell lines transfected with SIRT4 plasmid or SIRT4-siRNA. SIRT4 inhibited lung cancer cell proliferation, blocked the cell cycle and repressed cell invasion and migration. Mitochondrial dynamics has been implicated in malignant properties of cells, particularly metastasis that is the major cause of death in patients diagnosed with cancer including lung cancer. This is the first study to identify an association between SIRT4 expression and decreased mitochondrial fission, which was driven by Drp1. SIRT4 inhibited Drp1 phosphorylation and weakened Drp1 recruitment to the mitochondrial membrane via an interaction with Fis-1. SIRT4 expression was lower in nodal metastatic tumor samples than their corresponding primary tumors, and cases with low expression of SIRT4 tended to have high p-Drp1 labeling. Also, MEK/ERK activity appeared to be hampered by SIRT4 expression, which may have implications for cells’ invasive capacities. In conclusion, our findings suggest that SIRT4 functions as an important antitumor protein in NSCLC, and should be investigated further with respect to future anticancer strategies.

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