The Role Of Sumo-specific Protease 1(SENP1) In Cellular Senescence And Tumorigenesis

Serial passage of primary mammalian cells or strong mitogenic signals induces a permanent exit from the cell cycle called senescence.Senescence is thought to represent a defense mechanism against uncontrolled proliferation and cancer.Posttranslational modification with small ubiquitin-like modifier(SUMO)proteins is now established as one of the key regulatory protein modifications in eukaryotic cells.SUMO modifies many proteins that participate in diverse cellular processes,including transcriptional regulation,nuclear transport,maintenance of genome integrity,and signal transduction.Covalent attachment of SUMO to proteins is highly dynamic,and both SUMO–protein conjugation and cleavage can be regulated.Increased evidences show that the de-conjugation induced by SENPs plays a crucial role in determining the protein sumoylation status and activity.Some signaling proteins regulating cell senescence have been identified as SUMOylated proteins.However,it is largely unknown the role of SUMOylation in regulation of senescence as well as the molecular mechanism underlying senescence regulated by SUMOylation.We previously showed that SENP1 deficiency delayed the replicative senescence in MEF cells.Therefore,we proposed that SENP1 would play an important role in regulation of senescence.In this study,we show that SENP1-/-MEFs are refractory to H-Ras induced senescence.Overexpression of H-Ras increases the senescence in both of SENP1 +/+ and SENP1-/-MEFs.However,the senescence in H-Ras-transfected SENP1-/-MEFs are much less than that in H-Ras-transfected SENP1+/+ MEF cells.Meanwhile,H-Ras-transfected SENP1-/-MEFs show less proliferative ability and malignant transform than H-Ras-transfected SENP1+/+ cells.Mechanism studies show that SENP1 de-SUMOylates Bmi1 and reduces Bmi1 suppression of ARF/INK4 A locus,which enhances cell senescence and defenses cell malignant transformation.We further find that the SENP1 is positively associated with senescence marker p16 and HP1γ in Prostatic Intraepithelial Neoplasia tissue sample.This work illustrates the role of SENP1 in cellular senescence and the mechanism underlaying.It also suggests that SENP1 may play a vital role in preventing tumor development from pre-cancer lesion PIN to prostatic cancer.The conclusion of this research provides us a new perspective on the role of SENP1 in regulating cellular senescence and tumor development.