Evaluating the Radiosensitisation Potential of HDAC Inhibition by Dacinostat in High-Grade Meningioma Models

Authors

• Shahana Shaji, Peninsula Medical School

Abstract

Background:Meningioma is the most common primary intracranial tumour, and the lack of standard systemic treatments presents a therapeutic challenge in its management, making radiotherapy a crucial intervention for recurrent, high-grade, or inoperable tumours. Nonetheless, the inherent radioresistance of meningioma and the anatomical constraints of avoiding damage to adjacent neural tissues restrict dose escalation and therapeutic gains of radiotherapy. Histone deacetylases (HDACs) are mediators of radioresistance in meningioma, and their inhibition can be a rational approach to enhance the therapeutic efficacy.Methods:The study utilised dacinostat, a pan HDAC inhibitor, and explored the mechanistic aspects of radiosensitisation through assays for viability, survival, cell cycle progression, DNA damage, and apoptosis, supported by transcriptomic and proteomic profiling. The use of patient-derived primary meningioma cells in 3D settings further enhanced the translational relevance of this study.Results:This study demonstrated the radiosensitisation potential of dacinostat and its superior synergy with radiation compared to other FDA-approved HDACis. Pre-treatment with dacinostat effectively suppressed radiation-induced HDAC activity, resulting in sustained DNA damage, prolonged cell cycle arrest, and enhanced apoptosis. Mechanistic analyses revealed that radiosensitisation was associated with RAD51 downregulation, inhibition of DNA-PKcs activity, and modulation of p53 phosphorylation. Transcriptomic profiling revealed extensive transcriptional reprogramming under combination treatment, affecting cell cycle regulation and DNA repair pathways. Meanwhile, proteomic data highlighted the disruption of SUMOylation as a central mechanism of radiosensitisation and identified IFN-α/β in primary cells, suggesting a role in immune modulation. Importantly, in physiologically relevant 3D spheroid models, the combined treatment synergistically augmented cell death, supporting the translational potential of this therapeutic strategy.Conclusion:Overall, this study establishes dacinostat as a promising radiosensitiser that compromises DNA repair fidelity, thereby enhancing the efficacy of RT in meningioma. These findings provide a compelling preclinical basis for advancing dacinostat into clinical assessment for the management of aggressive meningioma.

Awarding Institution(s)

University of Plymouth

Supervisor

Juri Na, Sarah Kingdon, Jon Gil Ranedo

Document Type

Thesis

Publication Date

2026

Embargo Period

2026-05-20

Deposit Date

May 2026

Additional Links

https://doi.org/10.24382/z9n2-4354

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Recommended Citation

Shaji, S. (2026) Evaluating the Radiosensitisation Potential of HDAC Inhibition by Dacinostat in High-Grade Meningioma Models. Thesis. University of Plymouth. Available at: https://doi.org/10.24382/z9n2-4354