title: Class I histone deacetylases regulate p53/NF-κB crosstalk in cancer cells.
abstract: The transcription factors NF-κB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines promote signaling cascades that lead to the co-regulation of p53 and NF-κB. Consequently, nuclear p53/NF-κB signaling complexes activate NF-κB-dependent survival genes. The 18 histone deacetylases (HDACs) are epigenetic modulators that fall into four classes (I-IV). Inhibitors of histone deacetylases (HDACi) become increasingly appreciated as anti-cancer agents. Based on their effects on p53 and NF-κB, we addressed whether clinically relevant HDACi affect the NF-κB/p53 crosstalk. The chemotherapeutics hydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-κB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells. Using specific HDACi, we find that the class I subgroup of HDACs, but not the class IIb deacetylase HDAC6, are required for the hydroxyurea-induced crosstalk between p53 and NF-κB. HDACi decrease the basal and stress-induced expression of p53 and block NF-κB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53.
authors.affiliation: Friedrich-Schiller-University Jena, Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Hans-Knöll-Straße 2, 07745 Jena, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schäfer
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Göder
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kiweler
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Nisintha
authors.initials: N
authors.lastname: Mahendrarajah
authors.affiliation: Friedrich-Schiller-University Jena, Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Hans-Knöll-Straße 2, 07745 Jena, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Teodora
authors.initials: T
authors.lastname: Nikolova
authors.affiliation: Project Group "Personalized Tumor Therapy", Fraunhofer Institute of Toxicology and Experimental Medicine, Am Biopark 9, 93053 Regensburg, Germany.
authors.forename: Natasa
authors.initials: N
authors.lastname: Stojanovic
authors.affiliation: Friedrich-Schiller-University Jena, Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Hans-Knöll-Straße 2, 07745 Jena, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wieczorek
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Reich
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Tomicic
authors.affiliation: University Medicine Rostock, Department of General Surgery, Molecular Oncology and Immunotherapy, Schillingallee 35, 18057 Rostock, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.affiliation: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Kochstraße 2, 07745 Jena, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sonnemann
authors.affiliation: Department of Medicine V, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Dietrich
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sellmer
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040 Regensburg, Germany.
authors.forename: Siavosh
authors.initials: S
authors.lastname: Mahboobi
authors.affiliation: Friedrich-Schiller-University Jena, Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Hans-Knöll-Straße 2, 07745 Jena, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heinzel
authors.affiliation: Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, Ismaninger Straße 22, 81675 München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 67, 55131 Mainz, Germany. Electronic address: okraemer@uni-mainz.de.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004273:DNA, Neoplasm; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D006655:Histone Deacetylases; D014740:Vidarabine; C024352:fludarabine; D006918:Hydroxyurea
keywords: HDAC; HDACi; NF-κB; Replicative stress; Survivin; p53