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

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.
AuthorsYuan-Hua Wu, Chi-Wei Hong, Yi-Ching Wang, Wei-Jan Huang, Ya-Ling Yeh, Bour-Jr Wang, Ying-Jan Wang, Hui-Wen Chiu
JournalCancer letters (Cancer Lett) Vol. 400 Pg. 79-88 (08 01 2017) ISSN: 1872-7980 [Electronic] Ireland
PMID28450160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2017 Elsevier B.V. All rights reserved.
Chemical References
  • Acridines
  • Carrier Proteins
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Nuclear Proteins
  • TMU-35435
  • Topoisomerase II Inhibitors
  • Etoposide
  • RNF144A protein, human
  • Ubiquitin-Protein Ligases
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Prkdc protein, mouse
  • Proteasome Endopeptidase Complex
Topics
  • Acridines (pharmacology)
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Autophagy (drug effects)
  • Carrier Proteins (metabolism)
  • Cell Line, Tumor
  • DNA Damage
  • DNA End-Joining Repair (drug effects)
  • DNA-Activated Protein Kinase (metabolism)
  • DNA-Binding Proteins (metabolism)
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Etoposide (pharmacology)
  • Female
  • Histone Deacetylase Inhibitors (pharmacology)
  • Humans
  • Hydroxamic Acids (pharmacology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nuclear Proteins (metabolism)
  • Proteasome Endopeptidase Complex (metabolism)
  • Proteolysis
  • Time Factors
  • Topoisomerase II Inhibitors (pharmacology)
  • Triple Negative Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
  • Ubiquitin-Protein Ligases (metabolism)
  • Ubiquitination

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