SUMO Protease SENP3 Regulates Autophagy And Epithelial-Mesenchymal Transition:Mechanisms And Biological Significances

Cellular oxidative stress is closely related to various diseases.In normal cells and tumor cells,the oxidative stress may play an important role in autophagy and tumor metastasis.This study focuses on the regulation of autophagy and epithelial-mesenchymal transition under oxidative stress.It has been reported that oxidative stress positively regulated autophagy.Autophagy,a highly conserved process and fine-tuning regulation by protein complexes,can be modulated at the post-translational level in response to stress inducers promptly.Beclin1 is a critical component in the class III phosphatidylinositol 3-kinase(PtdIns3K)complex that contains VPS15,VPS34,UVRAG and other molecules to trigger autophagosome formation.Phosphorylation,ubiquitination and acetylation have been reported to regulate the function of Beclin1 in mediating the formation of PtdIns3 K complex.Whether SUMOylation can modify Beclin1 and thus regulate autophagy remains unknown.We found Beclin1 could bind with proteins needed for SUMOylation,Ubc9,SUMO3 and another facet of SUMO-specific protease SENP3.SUMOylation of Beclin1 benefited the formation of autophagosome through promoting Beclin1 interaction with UVRAG and the activity of VPS34.Of note,this type of modifications was enhanced under in vitro as well as in vivo starvation conditions.Meanwhile,SENP3 can also be induced and simultaneously mediated de-SUMOylation of Beclin1 which provided a negative regulation to autophagy and thus might prevent from excessive autophagic cell death under fatal stress conditions.The negative regulation mechanisms was verified using SENP3 silenced cells or liver tissues derived from heterozygously deleted mouse.Taken together,our study identifies a novel modification of Beclin1 and a self-control mechanism of autophagy,In addition,our study demonstrates the negative regulation of autophagy under oxidative stress.The impact of cellular oxidative stress in the epithelial-mesenchymal transition(EMT)development has been noticed,however,whether SUMOylation and SENP3 mediated de-SUMOylation could regulate EMT remains unknown.We found SENP3 could affect autophagy in gastric carcinoma cell and orthotopic gastric cancer model.We demonstrated that the expression of mesenchymal marker genes and cell migration ability were enhanced in SENP3-overexpressing gastric cancer cells and attenuated in SENP3-knockdown cells.Biochemical assays identified FOXC2 as a substrate of SENP3,Meanwhile N-cadherin was verified as a target gene of FOXC2.We found that SENP3 was increased in gastric cancer cells and potentiates the transcriptional activity of FOXC2 through de-SUMOylation,which in favor of the induction of specific mesenchymal gene expression in gastric cancer metastasis.In conclusion,the present study clarifes the mechanism by which oxidative stress promotes EMT by SUMOylation regulation.Taken together,protein SUMOylation and de-SUMOylation can regulate autophagy and epithelial-mesenchymal transition in reponse to oxidative stress.This dynamic modification is potential mechanisms by which important cellular process are promoted or inhibited,meanwhile SENP3 might become promising target to interfere with these cellular processes or related diseases.