Effect And Mechanism Of Sirtuin 7 Deacetylase On Occurrence And Progression In Prostate Cancer

Objectives: Overexpression of SIRT7 is associated with poor survival outcome of prostate cancer patients,by data mining and bioinformatics analysis from TCGA database.SIRT7,a deacetylase,is closely related to epigenetic regulation of tumors,and is generally upregulated in cancers.However,the underlying mechanisms of cell proliferation,cell metastasis,patients’ prognosis of prostate cancer(PCa)have yet to be fully elucidated.Therefore,the main purpose of this study was to explore the possible regulatory mechanisms as well as clinical connections in the initiation,progression,metastasis,and patient’ survival of PCa,to determine if SIRT7 could be used in the prognosis of patients.SIRT7 expression and function may provide new tools for prevention and treatment of prostate cancer in clinical practice.Methods: 492 PCa cases,including the SIRT7 m RNA expression and prognosis information of patients,from the TCGA database were acquired and analyzed using Tumor Immune Estimation Resource(TIMER),Gene Expression Profiling Interaction Analysis(GEPIA)and c Bio Portal online tools.Then,SIRT7 sh RNA(Sh-SIRT7)and a SIRT7 overexpression plasmid(OE-SIRT7)were independently transfected into the androgen-independent DU145 cell line.Lastly,experimentation of relevant cell phenotypes and biological processes were carried out to evaluate tumor growth and metastasis in the DU145 cell lines indicated above,including cell proliferation assays of CCK8 and EDU,colony formation assays,wound-healing assays,transwell invasion assays,quantitative RT-PCR,western blotting and co-immunoprecipitation(Co IP)assays.Results: Results of CCK8 assay and EDU assay of DU145 in Scrambled and SIRT7-KD group indicate that the proliferation rate was inhibited by the loss of SIRT7 expression in vitro.While the colony formation assays manifest that the number of colonies in SIRT7-KD cell lines were notably less than Scrambled ones in vitro.Downregulation of SIRT7 mediated the upregulation of CDKN2 A and downregulation of CDK1,which jointly caused cell cycle arrested in G0/G1 phrase and G2/M phrase.Moreover,knocking down SIRT7 may induce the downregulation of the expression of PARP1 and PARP1 dependent PARP9/DTX3 L protein complex,impairing the process of DNA damage repair(NHEJ)to some extent.Meanwhile,when SIRT7 was knocked down,the results of western blot show that the expression of SIRT1,total TP53 and acetylated TP53(Lys382)were also remarkably downregulated.In addition,SIRT7 knockdown increased the sensitivity of prostate cancer cells to doxorubicin(DOX)and docetaxel(DOC)in vitro.Conclusions: Consequently,proven by relevant experimentation and literature review,we may draw the conclusion that SIRT7 acts as a pro-oncogenic factor in the development of PCa and plays a significant role in regulating the biological processes of cell proliferation,cell cycle,cell apoptosis and DNA damage repair in PCa via the TP53/GADD45 A signaling pathway,or possibly by interacting with PARP1.Thus,SIRT7 could be a potential therapeutic target for PCa,while expression of SIRT7 may provide prognostic value in PCa patients and offer vital guiding significance to clinical treatment monitoring and diagnosing.