ORCID
- C. Oliver Hanemann: 0000-0002-1951-1025
Abstract
Background: External radiation therapy (RT) is often a primary treatment for inoperable meningiomas in the absence of established chemotherapy. Histone deacetylase 6 (HDAC6) overexpression, commonly found in cancer, is acknowledged as a driver of cellular growth, and inhibiting HDACs holds promise in improving radiotherapeutic efficacy. Downregulation of HDAC6 facilitates the degradation of β-catenin. This protein is a key element in the Wnt/β-catenin signalling pathway, contributing to the progression of meningiomas. Methods: In order to elucidate the associations and therapeutic potential of HDAC6 inhibitors (HDAC6i) in conjunction with RT, we administered Cay10603, HDAC6i, to both immortalised and patient-derived meningioma cells prior to RT in this study. Findings: Our findings reveal an increase in HDAC6 expression following exposure to RT, which is effectively mitigated with pre-treated Cay10603. The combination of Cay10603 with RT resulted in a synergistic augmentation of cytotoxic effects, as demonstrated through a range of functional assays conducted in both 2D as well as 3D settings; the latter containing syngeneic tumour microenvironment (TME). Radiation-induced DNA damage was augmented by pre-treatment with Cay10603, concomitant with the inhibition of β-catenin and minichromosome maintenance complex component 2 (MCM2) accumulation within the nucleus. This subsequently inhibited c-myc oncogene expression. Interpretation: Our findings demonstrate the therapeutic potential of Cay10603 to improve the radiosensitisation and provide rationale for combining HDAC6i with RT for the treatment of meningioma. Funding: This work was funded by Brain Tumour Research Centre of Excellence award to C Oliver Hanemann.
DOI
10.1016/j.ebiom.2024.105211
Publication Date
2024-06-24
Publication Title
eBioMedicine
Volume
105
Keywords
Cay10603, HDAC6 inhibition, Meningioma, Radiosensitiser, β-catenin nuclear translocation, Tumor Microenvironment/radiation effects, Meningioma/radiotherapy, DNA Damage/radiation effects, Humans, Wnt Signaling Pathway/drug effects, Histone Deacetylase 6/antagonists & inhibitors, beta Catenin/metabolism, Cell Line, Tumor, Histone Deacetylase Inhibitors/pharmacology, Meningeal Neoplasms/radiotherapy, Cell Proliferation/drug effects
Recommended Citation
Hanemann, C., Na, J., & Shaji, S. (2024) 'Targeting histone deacetylase 6 (HDAC6) to enhance radiation therapy in meningiomas in a 2D and 3D in vitro study', eBioMedicine, 105. Available at: https://doi.org/10.1016/j.ebiom.2024.105211
