SIRT7-mediated PCAF Deacetylation Is Required For P53-dependent Cell Cycle Arrest Upon Glucose Deprivation

Sirtuin 7?SIRT7?,a NAD⁺-dependent class?histone deacetylase,plays vital roles in glucose sensing and cell metabolism.However,the underlying regulatory mechanism needs to be further investigated.In this study,SIRT7 wide-type?WT?or SIRT7 knockout?KO?HCT116 cells are subjected to glucose deprivation and carried out cell cycle analysis.Unlike with WT counterparts,SIRT7?KO?cells fail to efficiently undergo cell cycle arrest,suggesting SIRT7serves as an important regulator in glucose deprivation-induced cell cycle arrest.To further validate the mechanism of this action using diverse biological methods.Cell cycle arrest is often mediated by accumulating of cell cycle inhibitor p21 expression.knockdown of SIRT7 using siRNA impairs p21 expression,whereas these changes are absent in HCT116^-/-?which lack p53?cells,suggesting SIRT7-mediated cell cycle is dependent on p53.In further study,SIRT7 enhances p53 protein stability but not mRNA levels.MDM2?murine double minute?,a key E3 ligase for p53.SIRT7 accelerates MDM2protein degradation is dependent on its deacetylase activity.Although SIRT7 interacts with MDM2,SIRT7 fails to deacetylate MDM2,suggesting SIRT7 regulates MDM2 protein degradation indirectly.p300/CBP-associated factor?PCAF?possesses E3 ligase activity for MDM2,PCAF regulates p53 stability through controlling MDM2 protein levels.In our work,SIRT7 interacts with PCAF,which is notably increased upon glucose deprivation.Meanwhile,SIRT7deacetylates PCAF at lysine 720 residue and subsequently augments PCAF binding to MDM2,leading to MDM2 accelerated MDM2 protein degradation.Therefore,SIRT7-mediated PCAF deacetylation increase p53 stability and activity through which initiates cell cycle arrest.Together,our study reveals the function of SIRT7-PCAF-p53 pathway in effectively arresting cell proliferation under low glucose availability and establish the underling regulatory mechanism of this action,and may provide the basis for novel approaches to treat cancer.