ArticleDrug design, development and therapy2026
Targeted Degradation of Histone Deacetylase 8 Using Proteolysis Targeting Chimeras Technology: A Promising Approach for Glioblastoma Treatment.
Article in Drug design, development and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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 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.
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