Decitabine promotes the differentiation of poorly differentiated gastric cancer cells and enhances the sensitivity of NK cell cytotoxicity via TNF-α

Poorly differentiated gastric cancer (PDGC) is characterized by high invasiveness, rapid progression, and poor prognosis for patients. Differentiation therapy has long been a promising approach by manipulating the differentiation state of tumor cells to inhibit tumor growth, offering fewer side effects. Decitabine (DAC), is known as an inhibitor of DNA methylation, thus reactivating the transcription of previously methylated silenced genes associated with differentiation to induce a more differentiated state. This study used the differentiation-inducing agents DAC to treat two PDGC cell lines, MKN45 and NUGC4, and explored the impact of DAC on cell proliferation and influence of their sensitivity to Natural Killer cells (NK cells) mediated cytotoxicity. The results demonstrated a significant reduction in cell proliferation, migration, and invasion without affecting cell viability after DAC treatment. Additionally, transcriptomic analysis revealed that DAC-treated PDGC cells upregulated multiple immune-related genes, including the gene encoding for tumor necrosis factor alpha (TNF-α). Co-culture study of NK cells and PDGC cells showed that DAC treatment enhanced the sensitivity of these cancer cells to NK cell-mediated cytotoxicity, and TNF-α played a crucial role in promoting NK cell cytotoxicity. Following the subcutaneous implantation of tumors in nude mice, DAC administration significantly inhibited the growth of PDGC tumors and induced the upregulation of differentiation related genes. In summary, DAC effectively reduces the malignant characteristics of the PDGC cells by promoting their transition towards a higher state of differentiation and enhancing their sensitivity to NK cell-mediated killing, providing new insights for the mechanisms of the antitumor effects of DAC.