Overcoming Drug Resistance by Disrupting HDAC1 Condensates in Glioblastoma

Glioblastoma (GBM) is one of the most common and aggressive primary brain tumors in adults, with an extremely poor prognosis and a median overall survival typically less than two years. Temozolomide (TMZ) is currently the only chemotherapeutic agent widely used in clinical practice and can prolong patient survival to some extent. However, approximately 90 percent of cases experience tumor recurrence due to acquired resistance. How to overcome TMZ resistance remains a major challenge in clinical treatment.

In a joint study led by Dr. DONG Peng's team from the State Key Laboratory of Biomedical Imaging Science and System, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences, and their collaborators from Sun Yat-sen University discovered that TMZ treatment induces the formation of HDAC1-CTCF condensates in GBM cells, leading to chromatin remodeling and enhanced DNA repair activity, thereby promoting acquired resistance to TMZ.

Moreover, the team identified the small-molecule compound Resminostat as a therapeutic agent capable of targeting these condensates, thereby restoring TMZ sensitivity in patient-derived xenograft (PDX) models of resistant GBM and effectively overcoming tumor resistance.

The findings published in Nature Chemical Biology on January 9.

Utilizing three-dimensional super-resolution imaging technology 3D-ATAC-STORM independently developed by Dr. Dong's team, the research team first observed a significant reduction in chromatin accessibility in TMZ-resistant GBM cells and systematically characterized their 3D genomic structural features. Further mechanistic studies revealed that the decreased chromatin accessibility in resistant cells is primarily attributed to TMZ-induced formation of HDAC1-CTCF condensates, which accumulate on chromatin and restrict local accessibility.

To explore drug intervention strategies, the team established a high-content screening system targeting HDAC1-CTCF condensates and identified that Resminostat can disrupt their formation. In PDX models of TMZ-resistant GBM, Resminostat reversed tumor resistance to TMZ, promoted DNA damage response, and inhibited tumor progression.

Moreover, Resminostat's effect on HDAC1-CTCF condensates does not depend on inhibiting HDAC1's classical histone deacetylase activity but rather on interfering with its intrinsically disordered region (IDR)-mediated phase separation process. Resminostat disrupts the formation and stability of HDAC1-CTCF condensates, thereby inhibiting the assembly of DNA repair complexes at damage sites, reducing DNA repair efficiency, and enhancing TMZ-induced DNA damage accumulation, ultimately overcoming tumor cell resistance.

This study reveals the key mechanism by which HDAC1-CTCF condensate-mediated chromatin remodeling and DNA repair contribute to TMZ resistance in glioblastoma, expanding the understanding of HDAC1’s biological functions. It also demonstrates that Resminostat can restore TMZ sensitivity by disrupting HDAC1-CTCF condensates, providing a new theoretical basis for targeting tumor condensates to overcome drug resistance.

Molecular mechanisms underlying the development of temozolomide resistance in glioblastoma and the ability of Resminostat to overcome this resistance. (Image by SIAT)