Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability

Min Wu Chao, Po Chen Chu, Hsiao Ching Chuang, Fang Hsiu Shen, Chih Chien Chou, En Chi Hsu, Lauren E. Himmel, Han Li Huang, Huang Ju Tu, Samuel K. Kulp, Che Ming Teng, Ching Shih Chen

研究成果: 雜誌貢獻文章

13 引文 (Scopus)

摘要

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.

原文英語
頁(從 - 到)1796-1807
頁數12
期刊Oncotarget
7
發行號2
DOIs
出版狀態已發佈 - 一月 1 2016
對外發佈Yes

指紋

Notch1 Receptor
Neoplastic Stem Cells
Protein Stability
Histone Deacetylase Inhibitors
Histone Deacetylases
Breast Neoplasms
Depsipeptides
Proteasome Inhibitors
Acetylation
Immunoprecipitation
Heterografts
Small Interfering RNA
Protein Isoforms
Pharmacology
Pharmaceutical Preparations
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Oncology

引用此文

Chao, M. W., Chu, P. C., Chuang, H. C., Shen, F. H., Chou, C. C., Hsu, E. C., ... Chen, C. S. (2016). Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability. Oncotarget, 7(2), 1796-1807. https://doi.org/10.18632/oncotarget.6427

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.

於: Oncotarget, 卷 7, 編號 2, 01.01.2016, p. 1796-1807.

研究成果: 雜誌貢獻文章

Chao, MW, Chu, PC, Chuang, HC, Shen, FH, Chou, CC, Hsu, EC, Himmel, LE, Huang, HL, Tu, HJ, Kulp, SK, Teng, CM & Chen, CS 2016, 'Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability', Oncotarget, 卷 7, 編號 2, 頁 1796-1807. https://doi.org/10.18632/oncotarget.6427
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. / Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability. 於: Oncotarget. 2016 ; 卷 7, 編號 2. 頁 1796-1807.
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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.",
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