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

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.

SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation

“…SIRT4 is located primarily in the mitochondrial matrix and involved in a variety of events in mitotic cells (Fu et al., 2016). Differential roles of SIRT4 have been reported in diverse cell types and multiple tissues.…”

Sirt4: A Multifaceted Enzyme at the Crossroads of Mitochondrial Metabolism and Cancer

“…Sirt4 mRNA levels are reduced in many human cancers, such as lung, pancreatic, ovarian, gastric, colorectal, prostate, renal, liver, and endometrial cancer as well as hematological tumors (33-45) ( Table 1). Lower levels of Sirt4 protein expression in tumor tissues are often associated with worse pathological grading and reduced survival in cancer patients, and Sirt4 KO mice display an increased incidence of spontaneous tumors (2,33,36,37,44,45,49).…”

Causal roles of mitochondrial dynamics in longevity and healthy aging

“…Recent studies on SIRT4 suggest that it drives mitochondrial fusion through negative regulation of fission proteins and positive regulation of fusion proteins. SIRT4 overexpression in lung cancer‐derived cell lines results in more fused mitochondria and reduced mitochondrial fission via downregulation of DRP1 expression and inhibition of Ser 616 phosphorylation . Further evidence for SIRT4 regulation of mitochondrial dynamics comes from another in vitro study in cell lines in which SIRT4 overexpression was observed to drive mitochondrial fusion and was associated with an enrichment of L‐OPA1, the fusion‐promoting long form of OPA1, relative to S‐OPA1 .…”