Changes in the epigenetic environment have been shown to play a crucial role in tumorigenesis and the subsequent spread of tumors. One of the primary epigenetic alterations in tumor cells involves changes in chromatin modifications such as H3K27 methylation, altering chromatin structure and transcriptional activity of many crucial genes. Key regulators of histone modification states are enzymes like EZH2 and JMJD3, which exhibit antagonistic actions in cells and are associated with numerous types of tumors, thus representing important therapeutic targets. Major inhibitors of these enzymes include compounds like GSK-J4, an inhibitor of JMJD3, and tazemetostat, an inhibitor of EZH2. These compounds have shown promising results in disrupting epigenetic mechanisms that support tumor growth by altering their epigenetic landscape and have much less systemic impact on the body compared to conventional therapies like cisplatin. In this study, we analyzed the impact of GSK-J4 and tazemetostat on the expression of JMJD3 protein and the expression of SP1 and STAT3 transcription factors in three cancer cell models with combined addition of cisplatin to investigate the potential for sensitization. Our results show a partial effect of GSK-J4 on changing JMJD3 protein expression and the expression of SP1 and STAT3, considering that most of these changes may be associated with the use of cisplatin in the experiments. Additionally, we observed a significant change in pSTAT3 protein expression in the nuclei of cancer cells after tazemetostat treatment, although statistical significance was not achieved in these changes. These findings suggest the need for further research to better understand the specific mechanisms of action of these inhibitors and their potential in cancer therapy, particularly in the context of epigenetic changes contributing to disease development.