Abstract
Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNAmediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 1796-1807 |
| Number of pages | 12 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jan 1 2016 |
| Externally published | Yes |
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Keywords
- Breast cancer
- Cancer stem cells
- Histone deacetylase 8
- Histone deacetylase inhibitors
- Notch1
ASJC Scopus subject areas
- Oncology
Cite this
Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability. / Chao, Min Wu; Chu, Po Chen; Chuang, Hsiao Ching; Shen, Fang Hsiu; Chou, Chih Chien; Hsu, En Chi; Himmel, Lauren E.; Huang, Han Li; Tu, Huang Ju; Kulp, Samuel K.; Teng, Che Ming; Chen, Ching Shih.
In: Oncotarget, Vol. 7, No. 2, 01.01.2016, p. 1796-1807.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability
AU - Chao, Min Wu
AU - Chu, Po Chen
AU - Chuang, Hsiao Ching
AU - Shen, Fang Hsiu
AU - Chou, Chih Chien
AU - Hsu, En Chi
AU - Himmel, Lauren E.
AU - Huang, Han Li
AU - Tu, Huang Ju
AU - Kulp, Samuel K.
AU - Teng, Che Ming
AU - Chen, Ching Shih
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNAmediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer.
AB - Here, we report a novel non-epigenetic function of histone deacetylase (HDAC) 8 in activating cancer stem cell (CSC)-like properties in breast cancer cells by enhancing the stability of Notch1 protein. The pan-HDAC inhibitors AR-42 and SAHA, and the class I HDAC inhibitor depsipeptide, suppressed mammosphere formation and other CSC markers by reducing Notch1 expression in MDA-MB-231 and SUM-159 cells. Interrogation of individual class I isoforms (HDAC1-3 and 8) using si/shRNAmediated knockdown, ectopic expression and/or pharmacological inhibition revealed HDAC8 to be the primary mediator of this drug effect. This suppression of Notch1 in response to HDAC8 inhibition was abrogated by the proteasome inhibitor MG132 and siRNA-induced silencing of Fbwx7, indicating Notch1 suppression occurred through proteasomal degradation. However, co-immunoprecipitation analysis indicated that HDAC8 did not form complexes with Notch1 and HDAC inhibition had no effect on Notch1 acetylation. In a xenograft tumor model, the tumorigenicity of breast cancer cells was decreased by HDAC8 knockdown. These findings suggest the therapeutic potential of HDAC8 inhibition to suppress Notch1 signaling in breast cancer.
KW - Breast cancer
KW - Cancer stem cells
KW - Histone deacetylase 8
KW - Histone deacetylase inhibitors
KW - Notch1
UR - http://www.scopus.com/inward/record.url?scp=84957717703&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957717703&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.6427
DO - 10.18632/oncotarget.6427
M3 - Article
C2 - 26625202
AN - SCOPUS:84957717703
VL - 7
SP - 1796
EP - 1807
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 2
ER -