LncRNA Dlx4os drives malignant transformation and phenotype switching in melanoma

Cutaneous melanoma, a highly aggressive and therapy-resistant skin cancer, is characterized by its remarkable cellular plasticity, enabling tumour cells to switch between different phenotypic states. This plasticity contributes to tumour heterogeneity and is regulated by key transcription factors. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators in melanoma progression, yet much remains to be explored regarding their role in phenotype switching. In this study, we analysed long non-coding RNAs (lncRNAs) across different murine melanoma cell lines, identifying a set of lncRNAs potentially involved in regulating melanoma phenotypic state through cis-regulation of neighbouring protein-coding genes. We demonstrated that the lncRNA Dlx4os regulates genes associated with melanoma plasticity, favouring a mesenchymal-like, undifferentiated state. Dlx4os knockdown redirected melanoma cells to a more differentiated and less malignant phenotype, confirmed by differential expression of phenotypic state markers (Sox10, Mitf, Tgfβ, Sox6, Mlana), reduced their invasive and migratory potential, and delayed tumour progression in vivo. Furthermore, we identified a human orthologue of Dlx4os. Our findings highlight the potential of Dlx4os as both a biomarker and therapeutic target, capable of modulating melanoma's phenotypic plasticity to influence treatment response and metastasis.