Abstract LB419: HDAC8 over-expression promotes drug resistance and alters chromatin architecture in melanoma cells

Abstract Background: BRAF and MEK inhibitors are standard treatments for patients with BRAF V600E-mutated melanoma. However, resistance to these therapies poses a significant challenge. Understanding the molecular mechanisms underlying this resistance is critical for the development of more effective treatment strategies. Objective: To investigate the role of histone deacetylase 8 (HDAC8) in drug resistance in melanoma and evaluate the potential of HDAC8 degradation as a therapeutic strategy. Methods: We utilized overexpression vector to examine the effects of HDAC8 in melanoma cells. The proliferative, migratory, and drug sensitivity phenotypes were assessed in HDAC8-overexpressing melanoma cells. Additionally, we tested YX862, a selective HDAC8 degrader, to explore its effects on HDAC8 activity and downstream cellular processes. Acetylation of SMC3, a cohesin complex protein, was measured, and genome-wide HiC analysis was employed to assess chromatin structural changes. Results: HDAC8 overexpression promoted a more proliferative and migratory phenotype in melanoma cells. Furthermore, HDAC8-overexpressing cells exhibited reduced sensitivity to BRAF and MEK inhibitors. YX862 treatment specifically degraded HDAC8, leading to increased acetylation of SMC3. Genome-wide HiC analysis revealed that changes in SMC3 acetylation altered the three-dimensional structure of chromatin, potentially contributing to drug resistance. Conclusion: These findings highlight the critical role of HDAC8 in melanoma progression and drug resistance. HDAC8 degraders like YX862 may offer a promising therapeutic approach to overcome resistance and inhibit melanoma progression by modulating key epigenetic and cellular pathways. Citation Format: Kanchan Gupta, Richard L. Bennett, Michael F. Emmons, Yufeng Xiao, Guangrong Zheng, Keiran S. Smalley, Jonathan D. Licht. HDAC8 over-expression promotes drug resistance and alters chromatin architecture in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB419.