Original ArticleHDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells

•HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype thus promoting radioresistance in glioblastoma cells.•HDAC4 and HDAC6 expression in glioblastoma patients negatively correlates with overall survival rates after radiation treatment.•HDAC4 and HDAC6 targeting radiosensitizes p53 wild type or mutant glioblastoma cell lines.•In glioblastoma cells, HDAC6 prevents radiation-induced apoptosis- or autophagy-cell death dependently by the 53 status.•In glioblastoma cells, HDAC4 prevents radiation-induced senescence-cell death in a p53 wild type dependent manner

The role of histone deacetylase (HDAC) 4 and 6 in glioblastoma (GBM) radioresistance was investigated. We found that tumor samples from 31 GBM patients, who underwent temozolomide and radiotherapy combined treatment, showed HDAC4 and HDAC6 expression in 93.5% and 96.7% of cases, respectively. Retrospective clinical data analysis demonstrated that high-intensity HDAC4 and/or HDAC6 immunostaining was predictive of poor clinical outcome. In vitro experiments revealed that short hairpin RNA-mediated silencing of HDAC4 or HDAC6 radiosensitized U87MG and U251MG GBM cell lines by promoting DNA double-strand break (DSBs) accumulation and by affecting DSBs repair molecular machinery. We found that HDAC6 knock-down predisposes to radiation therapy-induced U251MG apoptosis- and U87MG autophagy-mediated cell death. HDAC4 silencing promoted radiation therapy-induced senescence, independently by the cellular context. Finally, we showed that p53WT expression contributed to the radiotherapy lethal effects and that HDAC4 or HDAC6 sustained GBM stem-like radioresistant phenotype. Altogether, these observations suggest that HDAC4 and HDAC6 are guardians of irradiation-induced DNA damages and stemness, thus promoting radioresistance, and may represent potential prognostic markers and therapeutic targets in GBM.