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    標題: A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer
    作者: Wu, Yuan-Hua
    Hong, Chi-Wei
    Wang, Yi-Ching
    Huang, Wei-Jan
    Yeh, Ya-Ling
    Wang, Bour-Jr
    Wang, Ying-Jan
    Chiu, Hui-Wen
    貢獻者: Natl Cheng Kung Univ, Coll Med, Dept Environm & Occupat Hlth
    Natl Cheng Kung Univ, Coll Med,Natl Cheng Kung Univ Hosp, Dept Radiat Oncol
    Natl Cheng Kung Univ, Dept Pharmacol
    Natl Cheng Kung Univ, Inst Basic Med Sci
    Taipei Med Univ, Grad Inst Pharmacognosy
    Natl Cheng Kung Univ Hosp, Dept Occupat & Environm Med
    Chia Nan Univ Pharm & Sci, Dept Cosmet Sci
    Chia Nan Univ Pharm & Sci, Inst Cosmet Sci
    Asia Univ, Dept Biomed Informat
    China Med Univ,China Med Univ Hosp, Dept Med Res
    Taipei Med Univ, Coll Med, Grad Inst Clin Med
    Taipei Med Univ, Shuang Ho Hosp, Dept Internal Med
    關鍵字: DNA damage
    DNA repair
    Ubiquitin-proteasome system
    Triple-negative breast cancer
    日期: 2017-08-01
    上傳時間: 2018-11-30 15:50:09 (UTC+8)
    出版者: Elsevier Ireland Ltd
    摘要: Triple-negative breast cancer (TNBC) treatment offers only limited benefits, and it is very relevant given the significant number of deaths that it causes. DNA repair pathways can enable tumor cells to survive DNA damage that is induced by chemotherapeutic or radiation treatments. Histone deacetylase inhibitors (HDACi) inhibited DNA repair proteins. However, the detailed mechanisms for this inhibition remain unclear. In the present study, we investigated whether a newly developed HDACi, TMU-35435, could enhance etoposide cytotoxicity by inhibiting DNA repair proteins in triple-negative breast cancer. We found synergistic cytotoxicity following treatment of 4T1 cells with etoposide and TMU-35435. Furthermore, TMU-35435 enhances etoposide-induced DNA damage by inhibiting the DNA repair pathway (non-homologous end joining, NHEJ). TMU-35435 suppresses the NHEJ pathway through the ubiquitination of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). In addition, TMU-35435 ubiquitinated DNA-PKcs by inducing the interaction between RNF144A (an E3 ligase) and DNA-PKcs. The combined treatment induced apoptosis and autophagic cell death in 4T1 cells. In an orthotopic breast cancer model, combined treatment with TMU-35435 and etoposide showed anti-tumor growth through the increase of DNA damage and cell death. Taken together, our data suggest that TMU-35435 enhances etoposide cytotoxicity by regulating ubiquitin-proteasome system and inhibiting the DNA repair pathway in TNBC. (C) 2017 Elsevier B.V. All rights reserved.
    關聯: Cancer Letters, v.400, pp.79-88
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