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

Yuan Hua Wu, Chi Wei Hong, Yi Ching Wang, Wei Jan Huang, Ya Ling Yeh, Bour Jr Wang, Ying Jan Wang, Hui Wen Chiu

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)79-88
Number of pages10
JournalCancer Letters
Volume400
DOIs
Publication statusPublished - Aug 1 2017

Fingerprint

DNA-Activated Protein Kinase
Triple Negative Breast Neoplasms
Histone Deacetylase Inhibitors
Etoposide
DNA Repair
Catalytic Domain
DNA Damage
Ubiquitin-Protein Ligases
Ubiquitination
Autophagy
Cause of Death
Neoplasms
Proteins
Cell Death
Radiation
Apoptosis
Breast Neoplasms
Growth

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer. / Wu, Yuan Hua; Hong, Chi Wei; Wang, Yi Ching; Huang, Wei Jan; Yeh, Ya Ling; Wang, Bour Jr; Wang, Ying Jan; Chiu, Hui Wen.

In: Cancer Letters, Vol. 400, 01.08.2017, p. 79-88.

Research output: Contribution to journalArticle

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