Epigenetic modulation of BARD1 to enhance anti-VEGF therapy
Despite the clinical use of anti-vascular endothelial growth factor (VEGF) antibodies (AVAs) in cancer therapy, resistance frequently develops, leading to disease progression. To address this, we identify a previously unknown role for breast cancer type 1 susceptibility protein (BRCA1)-associated RING domain 1 (BARD1) in modulating AVA sensitivity. Epigenetic modulation-via global and targeted DNA methylation-reveals BARD1 as a key regulator of angiogenesis. Sequential treatment with azacytidine overcomes AVA resistance in vivo. To enable precise epigenetic reactivation, we develop a liposomal CRISPR-deactivated Cas9 (dCas9)-TET1 system guided by BARD1-targeting single-guide RNAs (sgRNAs). This platform achieves CpG-specific demethylation of the BARD1 promoter, restores expression, and enhances AVA response. Additionally, BARD1 restoration, through either dCas9-TET1 or small interfering RNA (siRNA), significantly reduces tumor growth in combination with AVA in ovarian cancer models. These findings uncover a previously unrecognized function of BARD1 in tumor angiogenesis and demonstrate the potential of gene-specific epigenetic targeting to overcome AVA resistance.
Journal
Cell Reports MedicineAuthors
Funding
Platelets promote growth of ovarian cancerRole of exosomal SPHK1 in ovarian cancer progressionHarnessing the power of exosomes for non-coding RNA deliveryNarodowa Agencja Wymiany Akademickiej Grant BPN/BEK/2021/1/00115National Natural Science Foundation of China Grant 81573022National Natural Science Foundation of China Grant 31530036Key Technologies Research and Development Program Grant 2016YFC0900100University of Texas MD Anderson Cancer Center Grant PR 180381Cancer Center Support GrantCancer Prevention and Research Institute of Texas Grant 649968Cancer Prevention and Research Institute of Texas Grant RR160021Türkiye Bilimsel ve Teknolojik Araştırma Kurumu FundingFoundation for Women's Cancer FundingAmerican Cancer Society FundingOvarian Cancer Research Alliance FundingTraining of Academic Gynecologic OncologistsNational Center for Advancing Translational Sciences Grant UL1TR003167National Center for Advancing Translational Sciences Grant TL1TR003169Peking University FundingTargeting Stromal Influences on Glutamine Addiction in Ovarian CancerDevelopmental Research ProgramUS Department of Defense Grant W81XWH-21-1-0361US Department of Defense Grant W81XWH-22-1-0138