Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF-β1/Smad3 signaling
Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF-β1/Smad3 signaling
复制标题
Sirtuin 6 通过灭活 TGF-β 1/Smad3 信号传导抑制特发性肺纤维化过程中上皮细胞向间质细胞的转变
DOI：
10.18632/oncotarget.17723
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发表时间：
2017-09-05
期刊：
影响因子：
--
通讯作者：
Zhou, Xue
中科院分区：
文献类型：
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作者：
Tian, Kunming;Chen, Panpan;Zhou, Xue
Sirt6 与衰老、癌症和新陈代谢的控制有关，已被证明具有抗心脏和肝脏纤维化的功能。然而，Sirt6 是否抑制特发性肺纤维化仍不清楚。已发现上皮向间质转化参与特发性肺纤维化的发病机制。在本研究中，Sirt6 的强制表达显着消除了 A549 细胞中 TGF beta 1 诱导的上皮间质转化样表型和细胞行为。此外，野生型 Sirt6 的过表达改善了 TGF-β 1/Smad3 信号通路的激活和 Smad3-Snail1 的结合，但没有组蛋白脱乙酰酶活性的突变型 Sirt6 (H133Y) 则没有改善。同时，野生型Sirt6而非突变型Sirt6的过表达也恢复了TGF-β1对上皮间质转化相关转录因子的上调。此外，体内研究表明，使用腺相关病毒注射对Sirt6进行肺部靶向递送可减弱博来霉素诱导的肺上皮向间质转化和纤维化。总体而言，我们的研究结果揭示了 Sirt6 在上皮间质转化过程中发挥着关键调节剂的作用，这表明 Sirt6 可能是特发性肺纤维化的一个有吸引力的潜在治疗靶点。
Sirt6 which is implicated in the control of aging, cancer, and metabolism, has been shown to have anti-fibrosis function in heart and liver. However, whether Sirt6 inhibits idiopathic pulmonary fibrosis remains elusive. Epithelial to mesenchymal transition has been found to be involved in the pathogenesis of idiopathic pulmonary fibrosis. In the present study, forced expression of Sirt6 significantly abrogated TGF beta 1-induced epithelial to mesenchymal transition-like phenotype and cell behaviors in A549 cells. Additionally, activation of TGF-beta 1/Smad3 signaling pathway and binding of Smad3-Snail1 were ameliorated by overexpression of wild-type Sirt6 but not mutant Sirt6 (H133Y) without histone deacetylase activity. Meanwhile, upregulation of epithelial to mesenchymal transition-related transcription factors by TGF-beta 1 were also restored by overexpression of wild-type Sirt6 but not mutant Sirt6. Furthermore, in vivo study showed that lung targeted delivery of Sirt6 using adeno-associated virus injection blunted bleomycin-induced pulmonary epithelial to mesenchymal transition and fibrosis. Overall, our findings unravel that Sirt6 acts as a key modulator in epithelial to mesenchymal transition process, suggesting Sirt6 may be an attractive potential therapeutic target for idiopathic pulmonary fibrosis.