Tumor-specific super-enhancer drives overexpression of EVI1/MECOM in ovarian cancer.

Epithelial ovarian cancer (OC) is frequently diagnosed at an advanced stage, and despite surgery and chemotherapy, 70-80 % of patients relapse and die. Overcoming therapy resistance, e.g. by identifying molecular drivers, remains a major challenge. EVI1/MECOM, a known oncogene linked to poor prognosis in leukemia, is almost universally overexpressed in OC, suggesting a role in carcinogenesis. We report that aberrant EVI1/MECOM expression in OC is driven by a previously undiscovered 3' regulatory element. This ∼200 kb non-coding region downstream of EVI1/MECOM, is the most frequent recurrent chromosomal abnormality in OC. It interacts with the EVI1/MECOM promoter, shows high H3K27 acetylation and displays two 1.5 kb core regulatory elements, which are bound by the transcription factors SOX17 and PAX8, two markers routinely used to identify OC. Our findings reveal a novel enhancer-mediated mechanism of EVI1/MECOM overexpression in OC, offering insights into epigenetic regulation and potential therapeutic targets. TEASER: A novel mechanism of EVI1/MECOM dysregulation in Ovarian Cancer, revealing a potential vulnerability for therapy.