【摘 要】
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ObjectiveTo study the nuclear protein association of high-mobility group box-1(HMGB1) and histone deacetylase 1(HDAC1), and the effect of interaction on radiosensitivity in human breast cancer cells.M
【机 构】
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100092 Tianjin,KeylaboratoryofRadiationMedicineandNuclearMedicine,InstituteofRadiationMedicine,Chine
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ObjectiveTo study the nuclear protein association of high-mobility group box-1(HMGB1) and histone deacetylase 1(HDAC1), and the effect of interaction on radiosensitivity in human breast cancer cells.
MethodsThe protein-protein interaction was determined by immunoprecipitation-Western blot and glutathione-S-transferase capture assays. Cell growth was examined by MTT (methyl thiazolyl tetrazolium)assay and clonogenic assay. Histone deacetylase activity was analyzed by histone deacetylase assay.
ResultsA significant increase of HMGB1 protein and radiosensitivity was observed in MDA-MB-231 and MDA-MB-468 cells transfected with a pCMV-Tag2B expression vector carrying with a full-length of HMGB1 cDNA. HMGB1 binding to HDAC1 was demonstrated as GST(glutathione S-transferase)-pull down and immunoprecipitation Western blot assay, and the association was elevated by irradiation. An LXCXE motif was required for the HMGB1-HADC1 interaction and HMGB1 radiosensitization. A significant difference of IC50 value was observed, for example, 1.8 and 2.2 Gy(wtHMGB1 transfectants, P<0.05), 3.6 and 3.8 Gy(HMGB1/C103F transfectants, P>0.05), both compared with 3.9 and 4.1 Gy(pCMV-Tag2B transfectants) in MDA-MB-231 and MDA-MB-468 cells, respectively. A specific HDAC1 inhibitor trichostatin A markedly reduced the HMGB1-mediated radiosensitivity, 0.5 Gy in the presence of trichostatin A versus 1.8 Gy in absence of trichostatin A in MDA-MB-231 transfectants, 1.2 Gy (with trichostatin A) versus 2.2 Gy (without trichostatin A) in MDA-MB-468 transfectants, P<0.05. Histone deacetylase activity was also detected in immunoprecipitates prepared from these cells with antibodies to HMGB1, and this activity was abolished by the histone trichostatin A.
ConclusionsThese results suggest a previous unanticipated role for HDAC1 in modification of HMGB1-mediated radiosensitivity by its direct interaction with HMGB1.
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