NSD2 and miRNAs as Key Regulators of Melanoma Response to Romidepsin and Interferon‐α2b Treatment

Background: We investigated the role of Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and microRNAs (miRNAs) in melanoma de-differentiation following Romidepsin and Interferon-α2b (RI) treatment. Melanoma is the most lethal form of skin cancer, and despite advancements in therapy, treatment resistance remains a major challenge. De-differentiation has been widely recognized as a key factor contributing to therapy resistance. Methods: RNA-seq and TCGA transcriptomic data were re-analyzed to identify miRNAs and NSD2 expressions. The functional impact of selected miRNAs was then investigated at the molecular and phenotypic levels using primary and immortalized cell lines. Results: Our findings demonstrate that RI treatment induces a de-differentiation process in primary melanoma cells, resembling that observed in therapy-resistant melanoma. This effect is particularly pronounced in cells with an intrinsic proliferative phenotype, where we observed significant downregulation of NSD2, a key epigenetic regulator implicated in multiple cancers. Additionally, we identified specific miRNAs as mediators of NSD2 downregulation, influencing melanoma cell viability and fitness. Conclusions: These findings provide new insights into the molecular mechanisms driving melanoma progression and highlight potential therapeutic targets to counteract treatment resistance.