Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma

Melanoma, the most lethal form of skin cancer, is commonly associated by mutations in the BRAF gene, particularly BRAFV600E, which drives tumor proliferation via ERK1/2 signaling cascade. While BRAF inhibitors initially demonstrate efficacy, therapeutic resistance remains a significant challenge. Emerging evidence implicates the cAMP signaling pathway, particularly the cAMP response element-binding protein (CREB) and its repressor, Inducible cAMP Early Repressor (ICER), in melanoma progression and drug resistance. ICER, a transcriptional repressor regulated via Ras/MAPK-mediated phosphorylation and ubiquitination, is degraded in melanoma, undermining its tumor-suppressive role. In a brafV600E; p53(loss of function) transgenic zebrafish (Danio rerio) model, we investigated the role of a ubiquitin-resistant ICER mutant (S35-41A-ICER) in tumor progression. Transgenic fish expressing S35-41A-ICER exhibited extended survival and reduced tumor invasiveness compared to wild-type ICER. RNA sequencing revealed dysregulation of CREB/CREM targets and compensatory pathways, including Rap1 and PI3K/AKT signaling, as well as candidate gene targets of ICER regulation, including the Protein Kinase A catalytic subunit prkacaa. Our findings suggest that a ubiquitin resistant ICER mitigates melanoma progression and represses oncogenic pathways in a brafV600E melanoma context. Summary StatementThis study shows that ubiquitin-resistant ICER mutant suppresses melanoma progression, prolongs survival in brafV600E zebrafish, revealing its potential as a tumor suppressor and therapeutic target in melanoma resistance.