HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells.
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 p53WTexpression 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.
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy. Electronic address: f.marampon@gmail.com.
Francesco
F
Marampon
Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy.
Francesca
F
Megiorni
Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Simona
S
Camero
Department of Movement, Human and Health Sciences, University of Rome Foro Italico, Rome, Italy.
Clara
C
Crescioli
Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy; Department of Oncology, Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
Heather P
HP
McDowell
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy.
Roberta
R
Sferra
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy.
Antonella
A
Vetuschi
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy.
Simona
S
Pompili
Department of Pathology, San Salvatore Hospital, Coppito, L'Aquila, Italy.
Luca
L
Ventura
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
Francesca
F
De Felice
Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy.
Vincenzo
V
Tombolini
Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Rome, Italy.
Carlo
C
Dominici
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy.
Roberto
R
Maggio
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy.
Claudio
C
Festuccia
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Coppito, L'Aquila, Italy.
Giovanni Luca
GL
Gravina
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000528:radiation effects; D001343:Autophagy / Q000528:radiation effects; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology / Q000528:radiation effects*; D010641:Phenotype; D034622:RNA Interference; D011836:Radiation Tolerance / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C400300:HDAC4 protein, human; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
Glioblastoma; HDAC4; HDAC6; Radioresistance; Radiotherapy