title: An epigenetic mechanism underlying doxorubicin induced EMT in the human BGC-823 gastric cancer cell.
abstract: The epithelial to mesenchymal transition (EMT) is a key step during embryonic morphogenesis and plays an important role in drug resistance and metastasis in diverse solid tumors. We previously reported that 48 h treatment of anti-cancer drug doxorubicin could induce EMT in human gastric cancer BGC-823 cells. However, the long term effects of this transient drug treatment were unknown. In this study we found that after 48 h treatment with 0.1 μg/ml doxorubicin, most cells died during next week, while a minor population of cells survived and formed colonies. We propagated the surviving cells in drug free medium and found that these long term cultured drug survival cells (abbreviated as ltDSCs) retained a mesenchymal-like cell morphology, and expressed high levels of EMT-related molecules such as vimentin, twist and β-catenin. The expression of chromatin reprogramming factors, Oct4 and c-myc, were also higher in ltDSCs than parental cells. We further demonstrated that the protein level of p300 was upregulated in ltDSCs, and inhibition of p300 by siRNA suppressed the expression of vimentin. Moreover, the ltDSCs had higher colony forming ability and were more drug resistant when compared to parental cells. Our results suggested that an epigenetic mechanism is involved in the EMT of ltDSCs.
authors.affiliation: Department of Immunology, Wuhan University School of Basic Medical Science, Wuhan, China E-mail : annie106xiong@hotmail.com, qpzhang@whu.edu.cn.
authors.forename: Rong-Fei
authors.initials: RF
authors.lastname: Han
authors.forename: Xiang
authors.initials: X
authors.lastname: Ji
authors.forename: Xing-Gao
authors.initials: XG
authors.lastname: Dong
authors.forename: Rui-Jing
authors.initials: RJ
authors.lastname: Xiao
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.forename: Qiu-Ping
authors.initials: QP
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D050881:E1A-Associated p300 Protein / Q000096:biosynthesis / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D014746:Vimentin / Q000096:biosynthesis; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: C489427:MYC protein, human; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D014746:Vimentin; D051176:beta Catenin; D004317:Doxorubicin; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human