title: siRNA silencing EZH2 reverses cisplatin-resistance of human non-small cell lung and gastric cancer cells.
abstract: Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. EHZ2 is involved in drug resistance and is overexpressed in drug-resistant cancer cell lines. In this study, we investigated the effects of EHZ2 on cisplatin -resistance in A549/DDP and AGS/DDP cells. EHZ2 mRNA and protein were found to be significantly overexpressed in A549/DDP and AGS/DDP cells, compared to parental cells. EHZ2 siRNA successfully silenced EHZ2 mRNA and protein expression. Proliferation was inhibited and drug resistance to cisplatin was improved. Flow cytometry showed that silencing of EHZ2 arrested A549/DDP and AGS/DDP cells in the G0/G1 phase, increasing apoptosis, rh-123 fluorescence intensity and caspase-3/8 activities. Silencing of EHZ2 also significantly reduced the mRNA and protein expression levels of cyclin D1 and MDR1,while up-regulating p15, p21, p27 and miR-218 in A549/DPP cells. Furthermore, silencing of EHZ2 also significantly increased the expression level of tumor suppressor factor miR-218. We also found down-regulating EHZ2 expression increased methylation in A549/DDP and AGS/DDP cells. This study demonstrates that drug resistance can be effectively reversed in human cisplatin-resistant lung and gastric cancer cells through delivery of siRNAs targeting EHZ2.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China E-mail : wengui_xutj@163.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Wang-Ying
authors.initials: WY
authors.lastname: Man
authors.forename: Qing-Wei
authors.initials: QW
authors.lastname: Zhang
authors.forename: Wen-Gui
authors.initials: WG
authors.lastname: Xu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D002945:Cisplatin