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

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

ABSTRACT 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, tre...

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Main Authors: Alessandro De Santis, Lucrezia De Santis, Francesca Rossi, Silvia Gasparini, Valerio Licursi, Vito Antonio Amico, Imerio Capone, Alessandra Fragale, Stefania D'atri, Lucia Gabriele, Carlo Presutti
Format: Article
Language:English
Published: Wiley 2025-05-01
Series:Cancer Medicine
Subjects:
epigenetic regulation
melanoma
microRNAs
NSD2
proliferative subtypes
Online Access:https://doi.org/10.1002/cam4.70917
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Summary:ABSTRACT 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.
ISSN:2045-7634

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