Transcriptional reprogramming by AP-1-bound cis-regulatory elements drives melanoma development

Malignant melanoma is characterized by high metastatic potential and cellular plasticity. Its progression is driven not only by genetic alterations but also by epigenetic repro-gramming and changes in the transcriptome, mediated by transcription factors. The AP-1 family favors an invasive cell state by facilitating processes such as angiogenesis and migration. However, the AP-1-driven regulatory landscape and its implications for melanoma plasticity remain poorly understood. Here, we further elucidate the role of the AP-1 members c-Jun and Fra-1 in enhancer-driven gene regulation during melanoma development. Integrative ChIP-seq and RNA-seq analyses revealed extensive enhancer reprogramming during tumor formation and significant upregulation of genes annotated to enhancers gained in melanoma cells. On average, half of these regions are directly bound by c-Jun/Fra-1, given a high AP-1 motif rate (~80%) and chromatin accessibility. Enhancer-regulated c-Jun/Fra-1 targets are functionally linked to an invasive phenotype and comprise well-known melanoma drivers involved in migration and EMT. Clinically, high c-Jun/Fra-1 and target gene expression correlate with poor survival in BRAF wild-type and NRAS mutant melanoma patients, highlighting c-Jun/Fra-1 as a potential biomarker and therapeutic target. Overall, our data identify c-Jun/Fra-1 as major drivers of melanoma development through enhancer-mediated transcriptional programs.