The Role Of EZH2、HOX And MYCN In The Pathogenesis Of MDS

Objection:EZH2 plays an important role in epigenetic modification,while the role of EZH2 in the myelodysplastic syndrome(MDS)is unknown.Studies have found that HOX gene is frequently activated in leukemia and MDS patients,and epigenetic modification,especially histone methylation and DNA methylation are the main reasons for the activation of HOX gene.Our study try to explore the role of EZH2 in the pathogenesis of MDS and whether EZH2 perform epigenetic modification to HOX.MYC family is closely related to EZH2 gene,and MYCN is a member of MYC family.MYCN is an oncogene with transcription factor activity,so we also studied the relationship between MYCN and EZH2Methods:Flow cytometry and qRT-PCR were performed to analyze the expression of EZH2 in different types of MDS patients,meanwhile the correlation between EZH2 expression and MD S prognosis was analyzed.Further,SNP array was performed to detect the genomic change of EZH2 in MDS patients,genomic qRT-PCR verified the results of SNP array.Correlation between EZH2 copy number and expression was analysised.In addition,we studied the influences of EZH2 on SKM-1 cell biological behavior and tumor growth.ChIP-on-ChIP and ChIP-qPCR were performed to analysis the H3K27me3 of HOX gene in MDS patients and EZH2 knockdown cell line.Then GEM was performed to detect the corelation between EZH2 and HOX,in addition,we studied the effects of H3K27 demethylating agents on SKM-1 cell apoptosis、the expression of EZH2 and HOX gene.Finally,the effects of MYCN on SKM-1 cells growth and the binding capacity of MYCN to the EZH2 promoter region were examinedResults:The expression of EZH2 was decreased in MDS patients and correlated with poor clinical prognosis,and genomic loss of EZH2 leaded to the reduction of EZH2 expression.EZH2 knockdown promoted the malignant phenotype of MDS drived cell line,accompanied with the decrease of H3K27me3 and activation of HOX gene.Downregulation of MYCN induced SKM-1 cell apoptosis and inhibited cell proliferation.MYCN regulated the expression of EZH2 by binding to the promoter region of EZH2Conclusions:Our study reveals that genomic loss of EZH2 causes the reduction of EZH2 expression and the activation of HOX gene,which is strongly related to the pathogenesis of MDS.H3K27 demethylating agents activate HOX gene expression,which may lead to the activation of oncogene;Besides,MYCN was found to participate in epigenetic regulation through affecting the PcG family and histone modification.The abnormality of MYCN-EZH2-HOX axis is strongly related to the pathogenesis of MDS.