The epithelial to mesenchymal transition (EMT) is a key step during embryonic morphogenesis and playsan important role in drug resistance and metastasis in diverse solid tumors. We previously reported that 48 htreatment 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 htreatment with 0.1 μg/ml doxorubicin, most cells died during next week, while a minor population of cellssurvived and formed colonies. We propagated the surviving cells in drug free medium and found that theselong 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 ofchromatin reprogramming factors, Oct4 and c-myc, were also higher in ltDSCs than parental cells. We furtherdemonstrated that the protein level of p300 was upregulated in ltDSCs, and inhibition of p300 by siRNAsuppressed the expression of vimentin. Moreover, the ltDSCs had higher colony forming ability and were moredrug resistant when compared to parental cells. Our results suggested that an epigenetic mechanism is involvedin the EMT of ltDSCs.