2. Academic Validation
  3. A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer

A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer

  • Cancer Lett. 2017 Aug 1:400:79-88. doi: 10.1016/j.canlet.2017.04.023.
Yuan-Hua Wu 1,  Chi-Wei Hong 2,  Yi-Ching Wang 3,  Wei-Jan Huang 4,  Ya-Ling Yeh 2,  Bour-Jr Wang 5,  Ying-Jan Wang 6,  Hui-Wen Chiu 7
Affiliations

Affiliations

  • 1 Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 2 Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 3 Department of Pharmacology, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
  • 4 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
  • 5 Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
  • 6 Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biomedical Informatics, Asia University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: yjwang@mail.ncku.edu.tw.
  • 7 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taiwan. Electronic address: leu3@tmu.edu.tw.
PMID: 28450160 DOI: 10.1016/j.canlet.2017.04.023
Abstract

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.

Keywords

DNA damage; DNA repair; Triple-negative breast cancer; Ubiquitin–proteasome system.

Figures
Products