title: Suberoylanilide hydroxamic acid represses glioma stem-like cells.
abstract: BACKGROUND
  Glioma stem-like cells (GSCs) are proposed to be responsible for high resistance in glioblastoma multiforme (GBM) treatment. In order to find new strategies aimed at reducing GSC stemness and improving GBM patient survival, we investigated the effects and mechanism of a histone deacetylases (HDACs) inhibitor, suberoylanilide hydroxamic acid (SAHA), since HDAC activity has been linked to cancer stem-like cell (CSC) abundance and properties.
  
  
  METHODS
  Human GBM cell lines were plated in serum-free suspension cultures allowed for sphere forming and CSC enrichment. Subsequently, upon SAHA treatment, the stemness markers, cell proliferation, and viability of GSCs as well as cellular apoptosis and senescence were examined in order to clarify whether inhibition of GSCs occurs.
  
  
  RESULTS
  We demonstrated that SAHA attenuated cell proliferation and diminished the expression stemness-related markers (CD133 and Bmi1) in GSCs. Furthermore, at high concentrations (more than 5 μM), SAHA triggered apoptosis of GSCs accompanied by increases in both activation of caspase 8- and caspase 9-mediated pathways. Interestingly, we found that a lower dose of SAHA (1 μM and 2.5 μM) inhibited GSCs via cell cycle arrest and induced premature senescence through p53 up-regulation and p38 activation.
  
  
  CONCLUSIONS
  SAHA induces apoptosis and functions as a potent modulator of senescence via the p38-p53 pathway in GSCs. Our results provide a perspective on targeting GSCs via SAHA treatment, and suggest that SAHA could be used as a potent agent to overcome drug resistance in GBM patients.
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 11031, Taiwan.|Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
authors.forename: Che-Chia
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 11031, Taiwan.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
authors.forename: Tsung-I
authors.initials: TI
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan.
authors.forename: Jr-Jiun
authors.initials: JJ
authors.lastname: Liu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, 35053, Taiwan.
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, 11031, Taiwan.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan.
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
authors.forename: Chiung-Yuan
authors.initials: CY
authors.lastname: Ko
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, 367 Sheng-Li Road, Tainan, 70456, Taiwan. kwang2@nhri.org.tw.
authors.forename: Kwang-Yu
authors.initials: KY
authors.lastname: Chang
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. chuangcy@tmu.edu.tw.|Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, 11031, Taiwan. chuangcy@tmu.edu.tw.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases
keywords: Apoptosis; GBM stem-like cells; Senescence; Suberoylanilide hydroxamic acid; p38; p53