TUBITAK Destekli Projelerden Çıkan Yayınlar Topluluğu
Published January 1, 2025 | Version v1
Journal article Open

Epigenetic modulation of BARD1 to enhance anti-VEGF therapy

Creators

  • 1. Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA
  • 2. Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA
  • 3. Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA
  • 4. Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA
  • 5. Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 USA

Description

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.

Files

bib-cf6ea249-3365-44bb-b087-15cc7ad2fc62.txt

Files (352 Bytes)

Name Size Download all
md5:260c20b2b29d0aed1528d7d501be5c24
352 Bytes Preview Download