Epigenetic modulation of BARD1 to enhance anti-VEGF therapy.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-09-16 Epub Date: 2025-09-03 DOI:10.1016/j.xcrm.2025.102329

Emine Bayraktar, Cristian Rodriguez-Aguayo, Elaine Stur, Sudhir Kumar, Lingegowda S Mangala, Nicholas B Jennings, Nazende Nur Bayram, Sara Corvigno, Amma Asare, Cristina Ivan, Mark S Kim, Thanh Chung Vu, Pahul Hanjra, Sangbae Kim, Adrian Lankenau Ahumada, Weichem Wu, Sanghoon Lee, Anna Szymanowska, Hulya Oztatlici, Marcos R Estecio, Ju-Seog Lee, Abhinav K Jain, Nidhi Sahni, John P Hagan, Stephen Baylin, Jinsong Liu, Gabriel Lopez-Berestein, Sunila Pradeep, Anil K Sood

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引用次数: 0

Abstract

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.

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BARD1的表观遗传调控增强抗vegf治疗。

尽管抗血管内皮生长因子（VEGF）抗体（AVAs）在癌症治疗中的临床应用，但经常出现耐药性，导致疾病进展。为了解决这个问题，我们确定了乳腺癌1型易感蛋白（BRCA1）相关环结构域1 （BARD1）在调节AVA敏感性中的作用。表观遗传调节-通过全局和靶向DNA甲基化-揭示BARD1是血管生成的关键调节因子。阿扎胞苷序贯治疗可克服AVA在体内的耐药性。为了实现精确的表观遗传再激活，我们开发了一种脂质体crispr失活的Cas9 (dCas9)-TET1系统，该系统由靶向bard1的单导rna （sgRNAs）引导。该平台实现了cpg特异性的BARD1启动子去甲基化，恢复了表达，增强了AVA应答。此外，在卵巢癌模型中，通过dCas9-TET1或小干扰RNA （siRNA）修复BARD1可显著降低AVA联合肿瘤生长。这些发现揭示了BARD1在肿瘤血管生成中以前未被认识到的功能，并证明了基因特异性表观遗传靶向克服AVA抗性的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.