Abstract 1475: HDAC8 as a critical regulator of cancer cell genome stability: therapeutic implications

Abstract In cancer cells, chromatin replication is often misregulated in part due to mutations in oncogenes and tumor suppressor genes, leading to increased replication stress and genomic instability. While this instability drives cancer progression, it also makes cancer cells more dependent on genome maintenance pathways, presenting a therapeutic target. A promising strategy is to exacerbate replication stress, causing lethal genome instability. We have developed a sensitive reporter to monitor replication stress via single-stranded DNA at stressed forks. Our earlier study identified Tousled-like kinases (TLKs) crucial for chromatin assembly during genome replication and discovered TLK inhibitors to treat cancers through increasing replication stress. Additionally, we recently uncovered histone deacetylase 8 (HDAC8) inhibitors that disrupt chromatin replication and compromise genome integrity, particularly when combined with checkpoint kinase inhibitors. In this presentation, I will show you how HDAC8 behaves as caretakers of genetic and epigenetic integrity and how we targeted replication stress to create cancer-specific synergistic vulnerabilities. Citation Format: Zih-Yao Yu, Wei-Jan Huang, Stanton Gerson, Sung-Bau Lee. HDAC8 as a critical regulator of cancer cell genome stability: therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1475.