Selective histone deacetylase inhibition as a therapeutically relevant strategy in H3K27M-glioma
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ID: 318877
2026
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Abstract
BACKGROUND: Diffuse midline glioma (DMG) is a lethal pediatric brain tumor, driven by profound epigenetic dysregulation, raising the possibility that targeting epigenetic regulators such as histone deacetylases (HDACs) could provide a therapeutic benefit. However, despite preclinical activity, currently available HDAC inhibitors have shown limited clinical translation due to poor central nervous system (CNS) penetration and a lack of HDAC isoform selectivity. METHODS: We combined CRISPR/Cas9 screening and pharmacologic HDAC inhibition to identify isoform-specific dependencies in DMG cell lines. Mechanistic studies were performed using bulk RNA-seq and HiChIP, and therapeutic efficacy was evaluated in orthotopic patient-derived xenograft mouse models. RESULTS: We identify that the nuclear-localized Class I HDAC isoforms are dependencies in DMG and demonstrate that HDAC2 represents a selective dependency that is highly expressed in patient tumors. We further identify a CNS-penetrant HDAC inhibitor, Compound 26, with preferential HDAC1/2 isoform selectivity. Transcriptomic and chromatin conformation analyses reveal that Compound 26 induces rapid transcriptional reprogramming, restores physiologic pontine histone patterns, and induces cell cycle arrest through chromatin reorganization. Consistent with these effects, Compound 26 slows DMG growth in vitro and in orthotopic in vivo models. CONCLUSIONS: Our findings establish HDAC2 as a critical and therapeutically actionable dependency in DMG. Genetic or pharmacological targeting of HDAC2 disrupts DMG chromatin architecture and induces cell cycle arrest. The HDAC1/2-selective inhibitor Compound 26 exhibits favorable CNS-penetration, tolerability, and antitumor activity in disease-relevant patient-derived xenograft models. Collectively, these data support isoform-selective HDAC inhibition as a rational strategy to overcome the translational limitations of pan-HDAC inhibitors in DMG.
| Reference Key |
openalex_W7166013873
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| Authors | Andrew Groves, Orville O. Kirkland, Costanza Lo Cascio, Xiuqi Wang, Caleb Heaslip, Joana G. Marques, Chen Song, Rebecca Poetschke, Tingjian Wang, Diana Chin, Yaw Asante, Qi Liu, Hyunmin Kim, Shanqing Gu, Maria Trissal, Jenna Labelle, Gustavo Alencastro Veiga Cruzeiro, Kristen L. Jones, Amy Cameron, Louise Clark, Brittaney Leeper, Quang-De Nguyen, Berkley E. Gryder, Mariella G Filbin, Jun Qi |
| Journal | journal of neuro-oncology |
| Year | 2026 |
| DOI |
10.1093/neuonc/noag142
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| URL | |
| Keywords | Keywords not found |
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