Histone H2AX sensitizes glioma cells to genotoxic stimuli by recruiting DNA double-strand break repair proteins.
Glioblastoma is a life-threatening tumor in the human brain despite the fact that radio-chemotherapy inducing DNA damage has been improved in the last decade. Various studies focusing on the enhancement of the susceptibility of glioblastoma cells to DNA damage have been reported, which are aimed at more efficient treatment for the tumor. In this study, we show that radioresistant T98G glioblastoma cells can develop sensitivity to DNA damage induced by irradiation and etoposide as a result of the introduction of a DNA repair-associated histone, H2AX. Interestingly, when H2AX-transformed T98G cells were irradiated, Brca1 and Nbs1 were readily recruited in DNA double-strand break (DSB) foci and showed the G2/M-phase arrest of the cell cycle. Moreover, up-regulation of Brca1 was observed in H2AX-T98G cells after exposure to irradiation. Together with the evidence that H2AX transfection does not affect growth activities of non-tumor cells under genotoxic stimuli, this suggests that H2AX gene transfer would provide a new modality for radio-chemotherapy for glioblastomas, probably through overcoming the instability of the genome, and that Brca1 and Nbs1 might be crucial in this methodology.
Momota
Hiroyuki
H
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
Ichimiya
Shingo
S
Kondo
Nobuhiko
N
Kikuchi
Tomoki
T
Torigoe
Toshihiko
T
Yamaki
Toshiaki
T
Houkin
Kiyohiro
K
Sato
Noriyuki
N
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000494:pharmacology*; D006801:Humans; D008938:Mitosis; D009152:Mutagenicity Tests; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014965:X-Rays
D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; C468783:H2AX protein, human; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; D005047:Etoposide