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. However, around 90 percent of cases experience tumor recurrence due to acquired resistance. How to overcome TMZ resistance remains a challenge.

In a study published in Nature Chemical Biology on Jan. 9, Dr. DONG Peng's team from the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences and the collaborators from Sun Yat-sen University discovered that TMZ treatment induces the formation of HDAC1-CTCF condensates in GBM cells, and they identified the small-molecule compound Resminostat as a therapeutic agent capable of targeting these condensates.

Through three-dimensional (3D) super-resolution imaging independently developed by Dr. DONG's team, the researchers observed a significant reduction in chromatin accessibility in TMZ-resistant GBM cells. They characterized their 3D genomic structural features, and 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 researchers established a high-content screening system targeting HDAC1-CTCF condensates, and identified that Resminostat can disrupt their formation. In patient-derived xenograft models of TMZ-resistant GBM, Resminostat reversed tumor resistance to TMZ, promoted DNA damage response, and inhibited tumor progression.

Moreover, the researchers found that Resminostat's effect on HDAC1-CTCF condensates depends on interfering with its intrinsically disordered region-mediated phase separation process. Resminostat disrupts the formation and stability of HDAC1-CTCF condensates, 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 GBM. It also reveals that Resminostat can restore TMZ sensitivity by disrupting HDAC1-CTCF condensates, providing a new theoretical basis for targeting tumor condensates to overcome drug resistance.