title: Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability.
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/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.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.|Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Min-Wu
authors.initials: MW
authors.lastname: Chao
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.|Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Po-Chen
authors.initials: PC
authors.lastname: Chu
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Chuang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Fang-Hsiu
authors.initials: FH
authors.lastname: Shen
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chou
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: En-Chi
authors.initials: EC
authors.lastname: Hsu
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.|Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Himmel
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Han-Li
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Huang-Ju
authors.initials: HJ
authors.lastname: Tu
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.affiliation: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, Columbus, Ohio, USA.|Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D009757:Nylons / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D055550:Protein Stability; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D009757:Nylons; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D011758:Pyrroles; D051881:Receptor, Notch1; D012097:Repressor Proteins; C585734:SAHA-PIP-delta; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: Notch1; breast cancer; cancer stem cells; histone deacetylase 8; histone deacetylase inhibitors