Abstract
To elucidate the epigenetic mechanisms of drug resistance, epigenetically reprogrammed H460 cancer cells (R-H460) were established by the transient introduction of reprogramming factors. Then, the R-H460 cells were induced to differentiate by the withdrawal of stem cell media for various durations, which resulted in differentiated R-H460 cells (dR-H460). Notably, dR-H460 cells differentiated for 13 days (13dR-H460 cells) formed a significantly greater number of colonies showing drug resistance to both cisplatin and paclitaxel, whereas the dR-H460 cells differentiated for 40 days (40dR-H460 cells) lost drug resistance; this suggests that 13dR-cancer cells present short-term resistance (less than a month). Similarly, increased drug resistance to both cisplatin and paclitaxel was observed in another R-cancer cell model prepared from N87 cells. The resistant phenotype of the cisplatin-resistant (CR) colonies obtained through cisplatin treatment was maintained for 2–3 months after drug treatment, suggesting that drug treatment transforms cells with short-term resistance into cells with medium-term resistance. In single-cell analyses, heterogeneity was not found to increase in 13dR-H460 cells, suggesting that cancer cells with short-term resistance, rather than heterogeneous cells, may confer epigenetically driven drug resistance in our reprogrammed cancer model. The epigenetically driven short-term and medium-term drug resistance mechanisms could provide new cancer-fighting strategies involving the control of cancer cells during epigenetic transition.
Highlights
Drug resistance is the major cause of drug treatment failure in cancer patients, and its genetic mechanisms are well understood[1,2,3,4,5]
Reprogramming factors (OCT4, SOX2, KLF4, and MYC) in the form of mRNA were transfected into H460 cells for 22 days in reprogramming medium (R-medium) or conditioned-R-medium, and the reprogrammed cancer (Rcancer) cells were maintained in conditioned-Rmedium supplemented with B18R to obtain reprogrammed H460 cell (R-H460) clones
After the establishment of reprogrammed H460 cancer cells (R-H460) or reprogrammed N87 (R-N87) cells by the transfection of the mRNAs of reprogramming factors (OCT4, SOX2, KLF4, and MYC), the stem cell medium was withdrawn for various periods to induce epigenetic changes: the resulting 13dR-H460 and 13dR-N87 cells, for which the stem cell medium was withdrawn for 13 days, showed peak resistance to cisplatin and paclitaxel, and this drug resistance disappeared before 40 days, indicating that dR-cancer cells show only short-term drug resistance, which peaks at approximately 2 weeks
Summary
Drug resistance is the major cause of drug treatment failure in cancer patients, and its genetic mechanisms are well understood[1,2,3,4,5]. In drug resistance due to genetic mechanisms, the outgrowth of rare cancer cell variants among genetically heterogeneous cancer cells occurs after the acquisition of point mutations or copy-number. Epigenetic mechanisms have been posited as important factors in rapid cancer drug resistance acquisition[6,7,8]. The process of the development of drug resistance via epigenetic mechanisms has not been fully elucidated. Official journal of the Korean Society for Biochemistry and Molecular Biology. Poojan et al Experimental & Molecular Medicine (2020) 52:1102–1115. R-cancer cells could be a promising means of elucidating the process of drug resistance by epigenetic mechanisms. The single-cell analysis of the dR-cancer cells was performed to monitor changes in their heterogeneity
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