The Mechanism Of Cardiotoxicity Induced By Doxorubicin In Anti-cancer Chemotherapy

Doxorubicin,as the most commonly used chemotherapeutic agents against a broad spectrum of cancers,is limited due to its cardiotoxicity.Sirt6 is an NAD~+-dependent deacetylase,which plays a key role in regulating inflammation,metabolism and longevity.Although some studies have shown that Sirt6 can resist stress-induced cardiac hypertrophy,it is unclear whether and how Sirt6 protects the heart against DOX-induced cardiotoxicity.Here,we presented that Sirt6 transgenic mice exhibited antagonistic effects on DOX-induced cardiotoxicity but an increased survival rate.Cardiomyocyte apoptosis is one of the primary factors of DOX-induced heart failure.Transcription factor GATA4 is the key regulator to maintain the survival of cardiomyocyte,which decreases sharply at the early stage of DOX stress response.We found that Sirt6 overexpression prevented the reduction of GATA4 protein level and inhibited cardiomyocyte apoptosis in the heart.Mechanistically,Sirt6 interacts with GATA4,promotes its acetylation and enhances the chromatin binding capacity of GATA4.However,Sirt6 inhibitor and deacetylase-dead mutants hardly influenced Sirt6-induced increase of GATA4acetylation level.Sirt6 recruits Tip60 acetyltransferase,the latter is responsible for the acetylation on GATA4 lysine 328/330.DOX treatment interrupts the Tip60-Sirt6-GATA4 complex,subsequently suppresses transcriptional activity of GATA4 and results in cardiomyocyte apoptosis.The K328/330R mutation of GATA4 restrict the transcriptional activity of GATA4 and antagonize the myocardial protection mediated by Sirt6.Collectively,this study for the first time reveals deacetylase-independent function of Sirt6 serves as a co-activator of GATA4 to antagonize DOX-induced cardiotoxicity and protect heart function,which also provide a potential target for clinical intervention of cardiotoxicity...