A lncRNA–miRNA axis regulates the balance between proliferative and invasive states in melanoma

Abstract Melanoma is a highly aggressive malignancy characterized by significant phenotypic plasticity, allowing tumor cells to transit between different phenotypic states. This process, known as phenotype switching, drives metastasis and therapeutic resistance. While the primary transcriptional markers defining these states are well-established, the non-coding regulatory networks that stabilize these phenotypes remain incompletely understood. In this study, we identify the long non-coding RNAs (lncRNAs) LINC00504 and LINC00520 as key components of a multilayered regulatory circuit associated with the regulation of the proliferative/invasive melanoma subtypes. Functional assays reveal that experimental silencing of LINC00504 or LINC00520 in proliferative cells is sufficient to enhance the migratory and invasive capacity of melanoma cells, effectively mimicking the phenotype switch toward the invasive state. Mechanistically, these lncRNAs function as competing endogenous RNAs (ceRNAs) in the cytoplasm, where they sequester specific microRNAs to prevent the repression of mRNA targets, including MITF . Furthermore, we establish that MITF directly binds to the regulatory elements of both lncRNAs to drive their transcription, forming a positive feedback loop that reinforces the proliferative transcriptional program. Disruption of this MITF-lncRNA-miRNA axis facilitates the transition toward an invasive phenotype. Collectively, our findings highlight a novel integrated regulatory circuit that maintains melanoma cell state stability and suggest that targeting these non-coding components may provide a strategy to overcome phenotypic plasticity and therapeutic adaptability in melanoma.