BACKGROUND: Phenotypic plasticity and heterogeneity of melanoma cells arising from epigenetic regulation and the activity of transcription factors is pivotal in chemoresistance. Therefore, there it is necessary to explore the molecular mechanisms underlying resistance to alkylating agents, such as dacarbazine. AIM: This study aimed to analyze transcriptome profiles of B16 melanoma cells after in vivo treatment with dacarbazine to identify key clusters of differentially expressed genes and regulatory transcription factors associated with chemoresistance. METHODS: The study used a C57Bl/6 mouse model of B16 melanoma. The animals were randomly allocated into a control group and an experimental group, each with 12 mice. The experimental group was treated with dacarbazine at 50 mg/kg. Total RNA was extracted from tumor tissue, before high-throughput sequencing was performed. Data were subjected to bioinformatic processing for gene clustering and prediction of transcription factors for analyzing motifs in RNA sequences. RESULTS: NGS sequencing and bioinformatic analysis yielded 670 differentially expressed genes, which were organized into 12 functional clusters related to DNA repair, apoptosis, and cell cycle. A comprehensive analysis identified key transcription factors (RELB, IRF5/7/4, NANOG, SOX2, LEF1, and NFKB2) that regulate signaling pathways essential for maintaining pluripotency (p = 0.000001), Wnt (p = 0.000753), TGF-β (p = 0.002631), Toll-like receptors (p = 0.000776), and NF-κB (p = 0.044609) associated with B16 melanoma cell resistance to the alkylating agent dacarbazine in vivo. CONCLUSION: The findings of this study indicated that the epigenetic and transcription mechanisms of chemoresistance in melanoma cells involves maintenance of the stem cell phenotype, regulation of the immune response, and activation of the epithelial-mesenchymal transition.
Lapkina et al. (Sat,) studied this question.