Epigenetic regulation of melanoma phenotypic plasticity and therapeutic resistance [CRISPR Screen]

Here, we identify the SAGA chromatin-modifying complex as a critical epigenetic regulator that constrains melanoma phenotypic plasticity and preserves therapeutic vulnerability. Loss of SAGA-dependent epigenetic regulation disrupts lineage-associated chromatin states, leading to widespread transcriptional reprogramming and enhanced cellular adaptability.

As a consequence, SAGA-deficient melanoma cells exhibit increased phenotypic heterogeneity and acquire resistance to targeted therapy. Mechanistically, SAGA loss impairs histone acetylation–dependent control of gene expression programs linked to differentiation and stress responses, enabling the emergence of drug-tolerant cell states. Together, these findings establish SAGA as an epigenetic safeguard against melanoma cell-state plasticity and reveal how disruption of chromatin regulatory complexes promotes therapeutic resistance.