Upregulation of Statl-HDAC4 confers resistance to etoposide through enhanced multidrug resistance 1 expression in human A549 lung cancer cells

Despite efforts to develop efficient chemotherapeutic drug strategies to treat cancer, acquired drug resistance is a commonly encountered problem. In the present study, to investigate this phenomenon, human A549 lung cancer cells resistant to the topoisomerase inhibitor etoposide (A549RT-eto) were used and compared with A549 parental cells. A549RT-eto cells demonstrated increased resistance to etoposide-induced apoptosis when compared with A549 parental cells. Notably, A549RT-eto cells were observed to exhibit greater levels of histone deacetylase 4 (HDAC4), phospho-Statl and P-glycoprotein [P-gp; encoded by the multidrug resistance 1 (MDR1) gene], compared with A549 cells. To address whether HDAC4 protein is involved in etoposide resistance in A549 cells, A549RT-eto cells were treated with trichostatin A (TSA; an HDAC inhibitor) during etoposide treatment. The combined treatment was demonstrated to enhance etoposide-induced apqptosis and reduce expression levels of HDAC4, P-gp and phospho-Statl. In addition, the suppression of Stat1 with siRNA enhanced etoposide-induced apoptosis and reduced the expression levels of HDAC4 and P-gp, suggesting that Stat1 is essential in the regulation of resistance to etoposide, and in the upregulation of P-gp. Notably, TSA treatment reduced P-gp transcript levels but Stat1 siRNA treatment did not, suggesting that P-gp is regulated by HDAC at the transcriptional level and by Stat1 at the post-transcriptional level. These results suggest that the upregulation of Stat1 and HDAC4 determines etoposide resistance through P-gp expression in human A549 lung cancer cells.