Although last decades studies, the cancer treatment is still incomplete. Also, the decitabine (DAC) have shown clinical anti-cancer efficacy but their mechanism of action is unclear. Identification of the mechanism of drugs is necessary for effective chemotherapy. Here, we investigate the mechanism that how does DAC treatment lead to apoptosis. Recent studies have shown that DAC treatment results in increased expression of ERVs, which induces apoptosis by activating MDA5 . We find that another immune response protein PKR can also bind to ERVs and is involved in DAC-mediated cell death. In addition, we show that DAC treatment causes increased expression of many noncoding RNAs that can act as dsRNAs to activate immune response proteins. Furthermore, using RNAi screening system, we examined the contribution of different dsRNA binding proteins (dsRBPs) in the effectiveness of the DAC treatment. Our study reveals that DAC-mediated apoptosis is a consequence of complex interactions among different dsRBPs for access to their commonly binding noncoding dsRNAs.