SIRT3 Inhibits Prostate Cancer Metastasis And Its Mechanism

Prostate cancer is a common malignant tumor in males and its incidence and mortality rates are increasing year by year.Clinically,main treatments for prostate cancer are radical surgery,chemotherapy,radiotherapy and endocrine therapy including castration,androgen deprivation and androgen receptor mediated androgen blockade.With the progression of prostate cancer,the prostate cancer cells gradually evolve to be androgen independent and even progress to metastasis.Our lab has reported that SIRT3,an NAD~+histone deacetylase,restrained prostate cancer growth both in vitro and in vivo;however,its role in prostate cancer metastasis has not been revealed.In this study,we focus on the function of SIRT3 in metastatic prostate cancer and hopefully that SIRT3 could be a potential target for future clinical treatment of prostate cancer.Based on clinical dataset analysis and experiments employing molecular,cellular and animal studies,we obtained results that are summarized as follows:Firstly,based on analyses of microarray datasets,SIRT3 expression was significantly decreased in metastatic tissues compared with prostate tumor tissues.Compared with prostate cancer cells of lower metastatic potential,the protein level of SIRT3 was lower in those of higher metastatic potential.Secondly,we constructed prostate cancer cells with stably overexpressed and knock-down SIRT3 and we found that SIRT3 inhibited the epithelial-mesenchymal transition(EMT)and migration of prostatic cancer cells in vitro and their metastasis in vivo in orthotopic prostate cancer model.Mechanistically,SIRT3 activated PI3K/Akt pathway downstream gene,FOXO3A by attenuating Wnt/?-catenin pathway,thereby inhibiting EMT and migration of prostate cancer cells.To be specific,SIRT3 interacts with FOXO3A,promoting it shuttling from the cytoplasm to the nucleus,dephosphorylating FOXO3A and then activated FOXO3A.Besides,the inhibitory effect of SIRT3 on prostate cancer cells metastasis was weakened by transfection with siRNA-mediated knockdown of FOXO3A.In addition,SIRT3 suppressed the Wnt/?-catenin pathway,and Wnt/?-catenin pathway was also involved in SIRT3's inhibition of prostate cancer cell metastasis.Indeed,SIRT3's inhibitory effect on EMT and migration of prostate cancer cells can be rescued after applying Wnt/?-catenin activator LiCl,or boosted by Wnt inhibitor XAV939.To sum up,we revealed a novel mechanism for prostate cancer metastasis that involves SIRT3/Wnt/?-catenin/FOXO3A signaling to modulate EMT and cell migration.Our result provided a new idea for the treatment of metastatic prostate cancer after ineffective androgen therapy.