Integration of eccDNA and Transcriptomic Landscapes Uncovers LMO2 as a Therapeutic Target in Ovarian Cancer

Extrachromosomal circular DNAs (eccDNAs) are emerging as key mediators of oncogenic signaling and therapeutic resistance, yet their interplay with Epigenetic dysregulation in ovarian cancer remains poorly understood. Methods: This study investigates the molecular mechanisms linking Panobinostat-mediated HDAC inhibition to eccDNA dynamics and the adaptive activation of oncogenes. Results: Panobinostat treatment induced significant remodeling of eccDNA landscapes, with enrichment of mRNA- and lncRNA-derived eccDNAs. Integration of RNASeq and HDAC3-ChIPSeq 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. Conclusion: Our findings highlight a novel connection between HDAC-mediated epigenetic regulation and eccDNA-driven oncogene activation, suggesting that Panobinostat induces the adaptive pathways, including LMO2, to confer drug resistance in ovarian cancer. These insights provide a framework for developing targeted therapies and improving precision oncology in ovarian cancer.