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 language | English |
|---|---|
| Pages (from-to) | 79-88 |
| Number of pages | 10 |
| Journal | Cancer Letters |
| Volume | 400 |
| DOIs | |
| Publication status | Published - Aug 1 2017 |
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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 journal › Article
}
TY - JOUR
T1 - A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer
AU - Wu, Yuan Hua
AU - Hong, Chi Wei
AU - Wang, Yi Ching
AU - Huang, Wei Jan
AU - Yeh, Ya Ling
AU - Wang, Bour Jr
AU - Wang, Ying Jan
AU - Chiu, Hui Wen
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - DNA damage
KW - DNA repair
KW - Triple-negative breast cancer
KW - Ubiquitin–proteasome system
UR - http://www.scopus.com/inward/record.url?scp=85018380511&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018380511&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2017.04.023
DO - 10.1016/j.canlet.2017.04.023
M3 - Article
C2 - 28450160
AN - SCOPUS:85018380511
VL - 400
SP - 79
EP - 88
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
ER -