Attenuated DNA damage repair by trichostatin A through BRCA1 suppression.
Recent studies have demonstrated that some histone deacetylase (HDAC) inhibitors enhance cellular radiation sensitivity. However, the underlying mechanism for such a radiosensitizing effect remains unexplored. Here we show evidence that treatment with the HDAC inhibitor trichostatin A (TSA) impairs radiation-induced repair of DNA damage. The effect of TSA on the kinetics of DNA damage repair was measured by performing the comet assay and gamma-H2AX focus analysis in radioresistant human squamous carcinoma cells (SQ-20B). TSA exposure increased the amount of radiation-induced DNA damage and slowed the repair kinetics. Gene expression profiling also revealed that a majority of the genes that control cell cycle, DNA replication and damage repair processes were down-regulated after TSA exposure, including BRCA1. The involvement of BRCA1 was further demonstrated by expressing ectopic wild-type BRCA1 in a BRCA1 null cell line (HCC-1937). TSA treatment enhanced radiation sensitivity of HCC-1937/wtBRCA1 clonal cells, which restored cellular radiosensitivity (D(0) = 1.63 Gy), to the control level (D(0) = 1.03 Gy). However, TSA had no effect on the level of radiosensitivity of BRCA1 null cells. Our data demonstrate for the first time that TSA treatment modulates the radiation-induced DNA damage repair process, in part by suppressing BRCA1 gene expression, suggesting that BRCA1 is one of molecular targets of TSA.
Zhang
Yin
Y
Division of Radiation Research, Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Carr
Theresa
T
Dimtchev
Alexandre
A
Zaer
Naghmeh
N
Dritschilo
Anatoly
A
Jung
Mira
M
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004247:DNA / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication; D015536:Down-Regulation / Q000187:drug effects* / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051721:Rad52 DNA Repair and Recombination Protein / Q000378:metabolism
D019313:BRCA1 Protein; C468783:H2AX protein, human; D006657:Histones; D006877:Hydroxamic Acids; C497194:RAD52 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; C012589:trichostatin A; D004247:DNA