Systematic multivariate analysis of chromatin complex dependencies reveals Set1C/COMPASS as a melanoma-enriched epigenetic vulnerability

Cancer cells often rely on abnormal regulation of gene activity to support uncontrolled growth and survival. This regulation is controlled not only by genetic mutations, but also by epigenetic mechanisms, chemical and structural modifications to DNA and its associated proteins that determine which genes are turned on or off. Several therapies that target epigenetic regulators have shown promise, particularly in blood cancers. However, identifying which epigenetic mechanisms are most important in specific cancers remains challenging, especially because epigenetic regulators frequently work together as multi-protein complexes. In this study, we combine large-scale public datasets with computational modeling to systematically identify lineage-enriched epigenetic vulnerabilities across many cancer types. We found that certain epigenetic complexes are selectively important in specific cancer lineages. In melanoma, an aggressive skin cancer, we identified a previously unrecognized dependence on a protein complex that modifies chromatin at gene promoters. We show that disrupting this complex impairs gene programs that drive cell division and blocks cancer cell growth. Our findings reveal a lineage-specific epigenetic vulnerability in melanoma and demonstrate how integrative computational approaches can uncover new targets for potential cancer therapy studies.