Oncotarget

Research Papers:

Sirtuin 6 inhibits epithelial to mesenchymal transition during idiopathic pulmonary fibrosis via inactivating TGF-β1/Smad3 signaling

Kunming Tian, Panpan Chen, Zhiping Liu, Shutian Si, Qian Zhang, Yong Mou, Lianyong Han, Qin Wang and Xue Zhou _

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Oncotarget. 2017; 8:61011-61024. https://doi.org/10.18632/oncotarget.17723

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Abstract

Kunming Tian1, Panpan Chen1, Zhiping Liu2, Shutian Si3, Qian Zhang1, Yong Mou4, Lianyong Han1, Qin Wang1 and Xue Zhou1

1Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, USA

3The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

4Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases, Chinese Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Correspondence to:

Xue Zhou, email: xue.zhou@hust.edu.cn

Keywords: Sirt6, epithelial to mesenchymal transition, TGF-β1/Smad3, idiopathic pulmonary fibrosis, adeno-associated virus

Received: December 22, 2016     Accepted: April 19, 2017     Published: May 09, 2017

ABSTRACT

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-β1-induced epithelial to mesenchymal transition-like phenotype and cell behaviors in A549 cells. Additionally, activation of TGF-β1/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-β1 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.


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