Targeted Degradation of Histone Deacetylase 8 Using Proteolysis Targeting Chimeras Technology: A Promising Approach for Glioblastoma Treatment
2
Issued Date
2026-01-01
Resource Type
eISSN
11778881
Scopus ID
2-s2.0-105028556345
Journal Title
Drug Design Development and Therapy
Volume
20
Start Page
1
End Page
21
Rights Holder(s)
SCOPUS
Bibliographic Citation
Drug Design Development and Therapy Vol.20 (2026) , 1-21
Suggested Citation
Chotitumnavee J., Seemaung P., Settacomkul R., Sukprasert R., Itoh Y., Suzuki T., Srihirun S., Power C., Vivithanaporn P. Targeted Degradation of Histone Deacetylase 8 Using Proteolysis Targeting Chimeras Technology: A Promising Approach for Glioblastoma Treatment. Drug Design Development and Therapy Vol.20 (2026) , 1-21. 21. doi:10.2147/DDDT.S555228 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/114384
Title
Targeted Degradation of Histone Deacetylase 8 Using Proteolysis Targeting Chimeras Technology: A Promising Approach for Glioblastoma Treatment
Corresponding Author(s)
Other Contributor(s)
Abstract
Introduction: Histone deacetylase 8 (HDAC8) plays a role in glioblastoma progression, making it a promising therapeutic target. While HDAC8 inhibitors (HDAC8is) suppress glioblastoma growth and prolong survival in animal models, they do not eliminate HDAC8. In contrast, HDAC8-targeting proteolysis-targeting chimera (PROTAC), a selective HDAC8 degrader, induces proteasomal degradation of HDAC8 and thus eliminates all of its functions. Purpose: In this study, we investigated the antitumor activity and underlying mechanisms of a previously reported HDAC8 PROTAC in glioblastoma cells. Methods: Cytotoxicity in glioblastoma-derived U-87 MG, A172 and T98G cells and primary human astrocytes (PHA) was assessed via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assays. Live-cell imaging was performed using an Incucyte<sup>®</sup> Live-Cell Analysis System. Cell proliferation, cell cycle distribution, and apoptosis were analyzed using flow cytometry. HDAC8 and key regulators of cell cycle and apoptosis were quantified via Western blotting. Results: HDAC8 PROTAC effectively degraded HDAC8 and exhibited cytotoxic and antiproliferative effects in human glioblastoma cells, while demonstrating minimal toxicity in PHA. It induced S-phase arrest and reduced Cdk1, Cdk2, Cdk4, Cdk6, and cyclin B1 expression. It elevated caspase-3/7 activation, downregulated Bcl-2, induced apoptosis, and upregulated key endoplasmic reticulum (ER) stress response proteins, including BiP, XBP1s, CHOP, and p-JNK in U-87 MG glioblastoma cells. The HDAC8 PROTAC demonstrated stronger antitumor activity than HDAC8i and pan-HDACi vorinostat. Moreover, the HDAC8 PROTAC showed selective toxicity toward glioblastoma cells compared to primary human astrocytes. Conclusion: HDAC8 PROTAC selectively suppressed glioblastoma cell growth and viability by arresting the cell cycle and inducing ER stress-mediated apoptosis via the IRE1α/XBP1s–JNK–CHOP pathway. Hence, HDAC8 PROTAC is a potential therapeutic agent for glioblastoma treatment.