https://scholars.lib.ntu.edu.tw/handle/123456789/485635
標題: | Targeting histone deacetylase 4/ubiquitin-conjugating enzyme 9 impairs DNA repair for radiosensitization of hepatocellular carcinoma cells in mice | 作者: | CHIAO-LING TSAI Liu W.-L. Feng-Ming Hsu Yang P.-S. RUOH-FANG YEN KAI-YUAN TZEN ANN-LII CHENG PEI-JER CHEN CHIA-HSIEN CHENG |
公開日期: | 2018 | 出版社: | John Wiley and Sons Inc. | 卷: | 67 | 期: | 2 | 起(迄)頁: | 586-599 | 來源出版物: | Hepatology | 摘要: | Several strategies to improve the efficacy of radiation therapy against hepatocellular carcinoma (HCC) have been investigated. One approach is to develop radiosensitizing compounds. Because histone deacetylase 4 (HDAC4) is highly expressed in liver cancer and known to regulate oncogenesis through chromatin structure remodeling and controlling protein access to DNA, we postulated that HDAC4 inhibition might enhance radiation's effect on HCC cells. HCC cell lines (Huh7 and PLC5) and an ectopic xenograft were pretreated with HDAC inhibitor or short hairpin RNA to knock down expression of HDAC4 and then irradiated (2.5-10.0 Gy). We evaluated cell survival by a clonogenic assay; apoptosis by Annexin V immunofluorescence; γH2AX, Rad51, and HDAC4 by immunofluorescence staining; HDAC4, Rad51, and ubiquitin-conjugating enzyme 9 (Ubc9) in HCC cell nuclei by cell fractionation and confocal microscopy; physical interaction between HDAC4/Rad51/Ubc9 by immunoprecipitation; and the downstream targets of HDAC4 knockdown by immunoblotting. Both HDAC4 knockdown and HDAC inhibitor enhanced radiation-induced cell death and reduced homologous recombination repair of DNA double-strand breaks and protein kinase B activation, leading to increased apoptosis. HDAC4 knockdown with or without an HDAC inhibitor significantly delayed tumor growth in a radiation-treated xenograft model. Radiation stimulated nuclear translocation of Rad51 in an HDAC4-dependent manner and the binding of Ubc9 directly to HDAC4, which led to Ubc9 acetylation. Moreover, these effects were accompanied by HDAC4/Ubc9/Rad51 complex dissociation through inhibiting nuclear translocation. Conclusion: HDAC4 signaling blockade enhances radiation-induced lethality in HCC cells and xenografts. These findings raise the possibility that HDAC4/Ubc9/Rad51 complex in DNA repair may be a target for radiosensitization of HCC. (Hepatology 2018;67:586-599). ? 2017 by the American Association for the Study of Liver Diseases. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85038912110&doi=10.1002%2fhep.29328&partnerID=40&md5=6d6969efb50e1b9f87ac189bb0e8a92a https://scholars.lib.ntu.edu.tw/handle/123456789/485635 |
ISSN: | 0270-9139 | DOI: | 10.1002/hep.29328 | SDG/關鍵字: | histone deacetylase 4; histone deacetylase inhibitor; histone H2AX; lipocortin 5; protein kinase B; Rad51 protein; ubiquitin conjugating enzyme; ubiquitin conjugating enzyme 9; unclassified drug; HDAC4 protein, human; histone deacetylase; histone deacetylase inhibitor; protein kinase B; Rad51 protein; radiosensitizing agent; repressor protein; ubiquitin conjugating enzyme; ubiquitin-conjugating enzyme UBC9; animal cell; animal experiment; animal model; animal tissue; apoptosis; Article; carcinoma cell; cell death; cell fractionation; cell survival; clonogenic assay; confocal microscopy; controlled study; DNA repair; double stranded DNA break; downstream processing; enzyme activation; gene knockdown; immunoblotting; immunofluorescence test; immunoprecipitation; in vivo study; liver cell carcinoma; male; mouse; nonhuman; priority journal; protein targeting; radiosensitization; recombination repair; animal; DNA repair; drug effect; drug screening; human; liver cell carcinoma; liver tumor; metabolism; nucleocytoplasmic transport; tumor cell line; Active Transport, Cell Nucleus; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; DNA Repair; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Liver Neoplasms; Male; Mice; Proto-Oncogene Proteins c-akt; Rad51 Recombinase; Radiation-Sensitizing Agents; Repressor Proteins; Ubiquitin-Conjugating Enzymes; Xenograft Model Antitumor Assays |
顯示於: | 腫瘤醫學研究所 |
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