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Deacetylase-independent HDAC1 condensation defines temozolomide response in glioblastoma
Qinkai Zhang1,2, Ru Qiu1,3, Bing Lu4
1Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
Abstract:
Temozolomide is a standard-of-care therapeutic agent for glioblastoma. However, persons who initially respond well often experience a notable reduction in efficacy over time, with the underlying mechanisms remaining unclear. Here we demonstrate that the reduced response to temozolomide correlates with decreased chromatin accessibility, marked by reduced H3K27ac modification and alterations in chromatin loops. Mechanistically, temozolomide treatment upregulates histone deacetylase 1 (HDAC1) expression. Intriguingly, increased HDAC1 forms condensates independently of its deacetylase function. These condensates arise from multivalent interactions within the intrinsically disordered region and specific interactions with CCCTC-binding factor (CTCF), facilitating resistance to temozolomide by promoting the assembly of DNA repair complexes, even in the absence of direct deacetylase activity of HDAC1. Through phase-separation-based screening, we identified resminostat as an effective disruptor of HDAC1-CTCF condensates, thereby restoring temozolomide sensitivity in patient-derived xenograft models. Our findings introduce deacetylase-independent HDAC1 condensation as a distinct mechanism regulating temozolomide response, providing valuable insights into potential therapeutic strategies.
Insights
Glioblastoma patients develop resistance to temozolomide (TMZ) due to increased histone deacetylase 1 (HDAC1) forming condensates that promote DNA repair. Disrupting these condensates with resminostat can restore TMZ sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Temozolomide (TMZ) is a primary treatment for glioblastoma (GBM), but its efficacy diminishes over time.
- Mechanisms underlying TMZ resistance in GBM are not fully understood, hindering therapeutic development.
Purpose of the Study:
- To elucidate the molecular mechanisms behind reduced response to temozolomide in glioblastoma.
- To identify novel therapeutic targets for overcoming temozolomide resistance.
Main Methods:
- Analysis of chromatin accessibility (H3K27ac, chromatin loops) in response to temozolomide.
- Investigating the role of histone deacetylase 1 (HDAC1) expression and its condensate formation.
- Utilizing phase-separation-based screening to identify potential drug candidates.
- Testing identified compounds in patient-derived glioblastoma xenograft models.
Main Results:
- Reduced temozolomide response correlates with decreased chromatin accessibility and H3K27ac modification.
- Temozolomide treatment increases HDAC1 expression, leading to the formation of deacetylase-independent condensates with CTCF.
- These HDAC1-CTCF condensates promote DNA repair complex assembly, conferring temozolomide resistance.
- Resminostat effectively disrupts HDAC1-CTCF condensates, restoring temozolomide sensitivity in preclinical models.
Conclusions:
- Deacetylase-independent HDAC1 condensation represents a novel mechanism of temozolomide resistance in glioblastoma.
- Targeting HDAC1 condensation offers a promising strategy to re-sensitize glioblastoma to temozolomide therapy.
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