title: Activated p53 with Histone Deacetylase Inhibitor Enhances L-Fucose-Mediated Drug Delivery through Induction of Fucosyltransferase 8 Expression in Hepatocellular Carcinoma Cells.
abstract: BACKGROUND
  The prognosis of advanced hepatocellular carcinoma (HCC) is dismal, underscoring the need for novel effective treatments. The α1,6-fucosyltransferase (fucosyltransferase 8, FUT8) has been reported to accelerate malignant potential in HCC. Our study aimed to investigate the regulation of FUT8 expression by p53 and develop a novel therapeutic strategy for targeting HCC cells using L-fucose-mediated drug delivery.
  
  
  METHODS
  Binding sites for p53 were searched for within the FUT8 promoter region. FUT8 expression was assessed by immunoblotting. Chromatin immunoprecipitation (ChIP) assays were performed to analyze p53 binding to the FUT8 promoter. The delivery of Cy5.5-encapsulated L-fucose-liposomes (Fuc-Lip-Cy5.5) to a Lens Culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3)-expressing HCC cells was analyzed by flow cytometry. The induction of FUT8 by histone deacetylase inhibitor (HDACi) -inducing acetylated -p53 was evaluated by immunoblotting. Flow cytometric analysis was performed to assess whether the activation of p53 by HDACi affected the uptake of Fuc-Lip-Cy5.5 by HCC cells. The cytotoxicity of an L-fucose-bound liposome carrying sorafenib (Fuc-Lip-sorafenib) with HDACi was assessed in vivo and in vitro.
  
  
  RESULTS
  The knock down of p53 with siRNA led to decreased FUT8 expression. ChIP assays revealed p53 binds to the FUT8 promoter region. Flow cytometric analyses demonstrated the specific uptake of Fuc-Lip-Cy5.5 into AFP-L3-expressing HCC cells in a p53- and FUT8-dependent manner. HDACi upregulated the uptake of Fuc-Lip-Cy5.5 by HCC cells by increasing FUT8 via acetylated -p53. The addition of a HDACi increased apoptosis induced by Fuc-Lip-sorafenib in HCC cells.
  
  
  CONCLUSIONS
  Our findings reveal that FUT8 is a p53 target gene and suggest that p53 activated by HDACi induces Fuc-Lip-sorafenib uptake by HCC cells, highlighting this pathway as a promising therapeutic intervention for HCC.
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okagawa
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kohichi
authors.initials: K
authors.lastname: Takada
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Arihara
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kikuchi
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Osuga
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kamihara
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Hayasaka
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Usami
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Murase
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Miyanishi
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobune
authors.affiliation: Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D004357:Drug Synergism; D005643:Fucose / Q000494:pharmacology*; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008081:Liposomes; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D008081:Liposomes; D010671:Phenylurea Compounds; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D005643:Fucose; D000077157:Sorafenib; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase