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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 languageEnglish
Pages (from-to)1796-1807
Number of pages12
JournalOncotarget
Volume7
Issue number2
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

Keywords

  • Breast cancer
  • Cancer stem cells
  • Histone deacetylase 8
  • Histone deacetylase inhibitors
  • Notch1

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Chao, M. W., Chu, P. C., Chuang, H. C., Shen, F. H., Chou, C. C., Hsu, E. C., Himmel, L. E., Huang, H. L., Tu, H. J., Kulp, S. K., Teng, C. M., & 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