Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability
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Min-Wu Chao1,2, Po-Chen Chu1,3, Hsiao-Ching Chuang1, Fang-Hsiu Shen3, Chih-Chien Chou1, En-Chi Hsu1, Lauren E. Himmel1,4, Han-Li Huang2, Huang-Ju Tu2, Samuel K. Kulp1, Che-Ming Teng2, Ching-Shih Chen1,3
1Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA
2Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
3Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
4Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA
Ching-Shih Chen, e-mail: [email protected]
Keywords: cancer stem cells, breast cancer, histone deacetylase 8, histone deacetylase inhibitors, Notch1
Received: July 28, 2015 Accepted: November 16, 2015 Published: November 28, 2015
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/shRNA-mediated 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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