SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway
SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway
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SIRT4 通过 ERK-Drp1 通路介导的线粒体动力学抑制 NSCLC 的恶性进展
DOI：
10.1038/onc.2016.425
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发表时间：
2017-05-11
期刊：
影响因子：
8
通讯作者：
Li, Q.
中科院分区：
文献类型：
--
作者：
Fu, L.;Dong, Q.;Li, Q.
SIRT4因其在能量代谢中的去乙酰化酶活性而闻名，但对其在癌症发生中的作用知之甚少。我们通过免疫组织化学染色证明在133例非小细胞肺癌（NSCLC）病例中有70例SIRT4表达降低，并通过共聚焦显微镜确定其定位于线粒体。SIRT4的低水平表达与肿瘤淋巴结转移（TNM）分期、肿瘤组织学类型（腺癌）、淋巴结状态、Ki - 67（增殖指数）以及较差的总体生存率相关。我们还研究了SIRT4在转染SIRT4质粒或SIRT4 - siRNA的肺癌细胞系中的生物学作用。SIRT4抑制肺癌细胞增殖，阻断细胞周期，并抑制细胞侵袭和迁移。线粒体动力学与细胞的恶性特性有关，特别是转移，转移是包括肺癌在内的癌症患者死亡的主要原因。这是第一项确定SIRT4表达与线粒体分裂减少之间关联的研究，这种线粒体分裂减少是由Drp1驱动的。SIRT4抑制Drp1磷酸化，并通过与Fis - 1的相互作用减弱Drp1向线粒体膜的募集。在淋巴结转移的肿瘤样本中SIRT4表达低于其相应的原发肿瘤，并且SIRT4低表达的病例往往具有较高的p - Drp1标记。此外，MEK/ERK活性似乎受到SIRT4表达的抑制，这可能对细胞的侵袭能力有影响。总之，我们的研究结果表明SIRT4在非小细胞肺癌中作为一种重要的抗肿瘤蛋白发挥作用，并且在未来的抗癌策略方面应进一步研究。
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.