Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation.
Histone acetyltransferases (HATs) regulate transcription, chromatin structure and DNA repair. Here, we utilized a novel HAT inhibitor, anacardic acid, to examine the role of HATs in the DNA damage response. Anacardic acid inhibits the Tip60 HAT in vitro, and blocks the Tip60-dependent activation of the ATM and DNA-PKcs protein kinases by DNA damage in vivo. Further, anacardic acid sensitizes human tumor cells to the cytotoxic effects of ionizing radiation. These results demonstrate a central role for HATs such as Tip60 in regulating the DNA damage response. HAT inhibitors provide a novel therapeutic approach for increasing the sensitivity of tumors to radiation therapy.
Sun
Yingli
Y
Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
Jiang
Xiaofeng
X
Chen
Shujuan
S
Price
Brendan D
BD
D048729:Anacardic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D009369:Neoplasms / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors
D048729:Anacardic Acids; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; C088115:anacardic acid; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases