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HDAC1 Condensate Formation – A Critical Mediator of Chemotherapeutic Resistance in Glioblastoma

By Stuart P. Atkinson, Ph.D.

May 27, 2026

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The Unexplored Role of Epigenetics in Treatment Resistance in Glioblastoma

Temozolomide represents the standard-of-care chemotherapeutic agent for the treatment of glioblastoma - a lethal primary brain tumor in adults. Unfortunately, most patients develop therapeutic resistance to this DNA damage-inducing alkylating agent and experience disease recurrence (Zhang et al.). While the mechanisms of temozolomide resistance remain incompletely defined, studies have identified an central role for epigenetic alterations (Weller et al.); therefore, exploring the implication of a range of epigenetic pathways – including alterations to 3D chromatin structure, histone modification profiles, and chromatin accessibility – could provide a means of better understanding resistance mechanisms and developing effective therapeutic strategies for glioblastoma patients.

The development of a super-resolved microscopy technique - 3D ATAC-PALM – had supported a spatial exploration of chromatin accessibility and its relationship to genome organization at the single-cell level, thanks to the combination of assay for transposase-accessible chromatin (ATAC) with fluorescent dye labeling and photoactivated localization microscopy (PALM) (Xie et al.). In their recent study, researchers led by Peng Dong (Chinese Academy of Sciences) and Wei Zhao (Sun Yat-sen University/Southern Medical University) moved beyond this previous advance and have now integrated a stochastic optical reconstruction microscopy (STORM) method (3D ATAC-STORM), used to enhance the spatial resolution of chromatin accessibility mapping (Fu et al.), with ATAC-seq, high-throughput chromosome conformation capture (Hi-C), and promoter capture Hi-C techniques to explore the influence of chromatin accessibility on temozolomide resistance in glioblastoma.

As reported in Nature Cell Biology, Zhang, Qiu, and Lu et al. took advantage of these myriad epigenetic assays to now link upregulated histone deacetylase 1 (HDAC1) expression, reduced levels of the permissive H3K27ac modification, altered chromatin looping, and liquid–liquid phase separation condensate formation to reduced responses to temozolomide treatment in glioblastoma. Overall, this study highlights HDAC1 condensate formation as a critical mediator of chemotherapeutic resistance in glioblastoma and proposes the targeting of condensate formation as a novel therapeutic strategy for glioblastoma treatment.

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HDAC1 Condensates – A New Player in Temozolomide Resistance

The analysis of primary glioblastoma cells revealed that the cellular stress induced by temozolomide treatment prompted the increased expression of HDAC1 - which targeted the removal of H3K27ac at open chromatin regions to induce a decrease in chromatin accessibility - and altered chromatin conformation within the nucleus. The authors note that the alterations to H3K27ac levels suggested the existence of broader modifications to the epigenetic landscape of glioblastoma cells, mediating the expression of transcriptomic programs that support adaptation/resistance to temozolomide treatment (Cavalli & Heard).

Unexpectedly, the study also uncovered a novel functional role for HDAC1 beyond this well-documented role in histone deacetylation; they discovered that the increased levels of HDAC1 promoted the formation of liquid–liquid phase separation condensates independently of deacetylation activity, which recruited the CCCTC-binding factor (CTCF) to previously unrecognized anchor sites and prompted the generation of aberrant chromatin loops. In detail, HDAC1–CTCF condensates promoted temozolomide resistance in glioblastoma cells by generating aberrant chromatin loops and facilitating the assembly of a DNA repair complex that includes 53BP1 and RAD51 at sites of temozolomide-induced DNA damage marked by γH2AX. Overall, the general increase in chromatin compaction and the improved site-specific DNA repair responses, supported by locally increased chromatin accessibility, likely significantly attenuate the desired anti-tumor DNA-damage-inducing function of temozolomide. The authors note that other HDACs have been reported to possess additional functions beyond their enzymatic activities – HDAC6 inhibits double-strand break repair, and HDAC3 activates proinflammatory genes in M1-like macrophages (Qiu et al. and Zhao et al.) – suggesting a degree of functional complexity in this protein family.

Finally, the authors employed phase-separation-based screening to identify resminostat – a safe and well-tolerated orally administered hydroxamate-type pan-inhibitor of class I and II HDAC enzymes (Brunetto et al.) - as an effective disruptor of HDAC1–CTCF condensates; encouragingly, resminostat treatment enhanced temozolomide sensitivity in patient-derived glioblastoma xenograft models by inhibiting enzymatic activity (thereby modulating H3K27ac levels) and HDAC1-CTCF condensate formation, thereby emphasizing the therapeutic promise of targeting these structures.

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HDAC1: An Epigenetic and Non-Epigenetic Therapeutic Target for Glioblastoma Treatment

Overall, this HDAC1-focused study reveals the formation of liquid–liquid phase separation condensates in response to temozolomide treatment in glioblastoma cells as a critical mechanism regulating therapeutic resistance; as such, this previously unrecognized regulatory mechanism may highlight a new means of improving treatment responses in patients suffering from this lethal primary brain tumor in adults. Indeed, the authors identify resminostat as a potentially effective therapeutic agent; however, the inability of this inhibitor to cross the blood–brain barrier and enter the central nervous system (Stamp et al.) may necessitate the exploration of alternative delivery approaches to ensure safe and effective treatment for temozolomide-resistant glioblastoma patients.

If histone deacetylation represents the focus of your epigenetic research, discover Active Motif's range of HDAC antibodies, kits, recombinant proteins, and small molecules to support all your epigenetic research needs.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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