KLF12 transcriptional activation by a novel LncRNA A930015D03Rik enhances melanoma metastasis.

Melanoma metastasis remains a poorly understood yet fatal hallmark of cancer progression, with limited therapeutic strategies targeting its underlying mechanisms. While the transcription factor KLF12 shows paradoxical roles across malignancies, its context-dependent functions in melanoma-particularly its regulatory interplay with extracellular vesicle (EV)-driven intercellular communication-have not been systematically explored. To address this gap, we investigated how metastatic melanoma cells exploit KLF12-mediated pathways through EV cargo transfer to propagate aggressive phenotypes. Our research results indicate that highly metastatic cells transfer lncRNA A930015D03Rik through exosomes, acting as a sponge for miR-204-5p, which promotes the expression of KLF12. The transcriptional activation of KLF12 facilitates the activation of critical pro-cancer pathways such as inflammation and NF-κB, while inhibiting the tumor-suppressive mechanisms of P53 and oxidative phosphorylation. This ultimately enhances the migration and invasion capabilities of low-metastatic tumor cells, driving the malignant progression of melanoma. In this study, we identified a novel tumor-derived EVs lncRNA, A930015D03Rik, which can enhance the expression of KLF12 through a ceRNA mechanism and influence the post-translational regulation of KLF12, thereby modulating the plasticity of tumor metastasis. This exosome-genome feedforward circuit explains KLF12's microenvironment-contingent pro-metastatic function, offering significant insights for the development of future therapeutic strategies targeting tumor metastasis.