ZNF582 hypermethylation promotes metastasis of nasopharyngeal carcinoma by regulating the transcription of adhesion molecules Nectin-3 and NRXN3

Background:Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma(NPC).However,the epigenetic mechanisms underlying NPC metastasis remains poorly understood.We aimed to find functional genes which regulate the metastasis of NPC and identify therapeutic targets for NPC treatment.Methods:Bisulfite pyrosequencing was used to analyze zinc finger protein 582(ZNF582)methylation in NPC tissues and cell lines.Quantitative reverse transcription-polymerase chain reaction(qRT-PCR)and Western blotting were used to determine the expression of ZNF582.In vitro and in vivo experiments were performed to evaluate the biological function of ZNF582 in NPC.ZNF582-targeting genes were identified by chromatin immunoprecipitation sequencing(ChIP-seq)and were confirmed by ChIP-qPCR and luciferase assay.Results:ZNF582 promoter was hypermethylated in NPC,and both the mRNA and protein levels of ZNF582 were down-regulated in NPC tissues and cell lines.The restoration of ZNF582 inhibited NPC migration,invasion,and metastasis,while the knockdown of ZNF582 promoted NPC migration,invasion,and metastasis in vitro and in vivo.ZNF582 directly regulated the transcription and expression of adhesion molecules Nectin-3 and NRXN3.Both Nectin-3 and NRXN3 were identified as functional targets of ZNF582,and the restoration or abrogation of these genes reversed the tumor suppressor effect of ZNF582 in NPC metastasis.Conclusions:ZNF582 acts as a tumor suppressor gene in NPC by regulating the transcription and expression of adhesion molecules Nectin-3 and NRXN3,which may provide novel therapeutic targets for NPC treatment.