title: Alteration of cancer stem cell-like phenotype by histone deacetylase inhibitors in squamous cell carcinoma of the head and neck.
abstract: Recent progression in the understanding of stem cell biology has greatly facilitated the identification and characterization of cancer stem cells (CSCs). Moreover, evidence has accumulated indicating that conventional cancer treatments are potentially ineffective against CSCs. Histone deacetylase inhibitors (HDACi) have multiple biologic effects consequent to alterations in the patterns of acetylation of histones and are a promising new group of anticancer agents. In this study, we investigated the effects of two HDACi, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on two CD44+ cancer stem-like cell lines from squamous cell carcinoma of the head and neck (SCCHN) cultured in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. Histone deacetylase inhibitors inhibited the growth of SCCHN cell lines in a dose-dependent manner as measured by MTS assays. Moreover, HDACi induced cell cycle arrest and apoptosis in these SCCHN cell lines. Interestingly, the expression of cancer stem cell markers, CD44 and ABCG2, on SCCHN cell lines was decreased by HDACi treatment. In addition, HDACi decreased mRNA expression levels of stemness-related genes and suppressed the epithelial-mesencymal transition phenotype of CSCs. As expected, the combination of HDACi and chemotherapeutic agents, including cisplatin and docetaxel, had a synergistic effect on SCCHN cell lines. Taken together, our data indicate that HDACi not only inhibit the growth of SCCHN cell lines by inducing apoptosis and cell cycle arrest, but also alter the cancer stem cell phenotype in SCCHN, raising the possibility that HDACi may have therapeutic potential for cancer stem cells of SCCHN.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chikamatsu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ishii
authors.forename: Takaaki
authors.initials: T
authors.lastname: Murata
authors.forename: Koichi
authors.initials: K
authors.lastname: Sakakura
authors.forename: Masato
authors.initials: M
authors.lastname: Shino
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyoda
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Masuyama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition; D006258:Head and Neck Neoplasms; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D010641:Phenotype; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; C497483:CD44 protein, human; D056572:Histone Deacetylase Inhibitors; D018960:Hyaluronan Receptors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; C528828:suberoyl bis-hydroxamic acid; C012589:trichostatin A