Integration of eccDNA and transcriptomic landscapes uncovers LMO2 as a therapeutic target in ovarian cancer

Extrachromosomal circular DNAs (eccDNA) are emerging as key mediators of oncogenic signaling and therapeutic resistance, yet their interplay with Epigenetic dysregulation in ovarian cancer remains poorly understood. This study investigates the molecular mechanisms linking Panobinostat (LBH589 ) -mediated HDAC inhibition to eccDNA dynamics and the adaptive activation of oncogenes. Panobinostat treatment induced significant remodeling of eccDNA landscapes, with enrichment of mRNA- and lncRNA-derived eccDNA. Integration of RNA-seq and HDAC3- ChIP-seq identified 52 eccDNA-linked, HDAC3-bound oncogenes upregulated by Panobinostat. Survival analysis revealed that alterations in these oncogenes correlated with worse disease-free survival in multiple cancer cohorts. Notably, our study revealed LMO2 as a novel oncogene in ovarian cancer. Our findings highlight a novel connection between HDAC-associated epigenetic regulation and eccDNA-linked oncogene activation, suggesting that Panobinostat treatment is associated with adaptive oncogenic responses, including LMO2 upregulation, which may modulate drug sensitivity in ovarian cancer.