Down Regulation of SIRT2 Reduced ASS Induced NSCLC Apoptosis Through the Release of Autophagy Components via Exosomes

Lei Wang; Pei Xu; Xiao Xie; Fengqing Hu; Lianyong Jiang; Rui Hu; Fangbao Ding; Haibo Xiao; Huijun Zhang

doi:10.3389/fcell.2020.601953

Down Regulation of SIRT2 Reduced ASS Induced NSCLC Apoptosis Through the Release of Autophagy Components via Exosomes

Front Cell Dev Biol. 2020 Dec 3:8:601953. doi: 10.3389/fcell.2020.601953. eCollection 2020.

Authors

Lei Wang¹, Pei Xu¹, Xiao Xie¹, Fengqing Hu¹, Lianyong Jiang¹, Rui Hu¹, Fangbao Ding¹, Haibo Xiao¹, Huijun Zhang²

Affiliations

¹ Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, China.

Abstract

Metastasis of cancer is the main cause of death in many types of cancer. Acute shear stress (ASS) is an important part of tumor micro-environment, it plays a crucial role in tumor invasion and spread. However, less is known about the role of ASS in tumorigenesis and metastasis of NSCLC. In this study, NSCLC cells were exposed to ASS (10 dyn/cm²) to explore the effect of ASS in regulation of autophagy and exosome mediated cell survival. Finally, the influence of SIRT2 on NSCLC cell metastasis was verified in vivo. Our data demonstrates that ASS promotes exosome and autophagy components releasing in a time dependent manner, inhibition of exosome release exacerbates ASS induced NSCLC cell apoptosis. Furthermore, we identified that this function was regulated by sirtuin 2 (SIRT2). And, RNA immunoprecipitation (RIP) assay suggested SIRT2 directly bound to the 3'UTR of transcription factor EB (TFEB) and facilitated its mRNA stability. TFEB is a key transcription factor involved in the regulation of many lysosome related genes and plays a critical role in the fusion of autophagosome and lysosome. Altogether, this data revealed that SIRT2 is a mechanical sensitive protein, and it regulates ASS induced cell apoptosis by modulating the release of exosomes and autophagy components, which provides a promising strategy for the treatment of NSCLCs.

Keywords: NSCLC; SIRT2; TFEB; acute shear stress; autophagy; exosome; metastasis.