title: CD47 activation-induced UHRF1 over-expression is associated with silencing of tumor suppressor gene p16INK4A in glioblastoma cells.
abstract: CD47, an integrin-associated protein is over-expressed in several tumors including glioblastomas. Activation of CD47 induces proliferation of human astrocytoma cells but not normal astrocytes via an Akt-dependent way. However, the pathways mediating this process are still unknown. The epigenetic integrator UHRF1 (Ubiquitin-like containing PHD and RING Finger 1) is over-expressed in various cancers and plays a vital role in the silencing of numerous tumor suppressor genes including p16(INK4A), thereby promoting cell proliferation. The aim of the present study was to investigate the role of UHRF1 and p16(INK4A) in CD47-induced effects. Herein we showed that activation of CD47 in human astrocytoma cell lines U87 and CCF- STTG1 (Grade IV), up-regulated the expression of UHRF1 with subsequent down-regulation of p16(INK4A), thus promoting cell proliferation. Blockage of CD47 using a blocking antibody down-regulated UHRF1 expression, accompanied by a re-expression of p16(INK4A), conducting to decreased cell proliferation in both cancer cell lines. Neither CD47 activation nor its blocking has any effect on UHRF1/p16(INK4A) expression in normal human astrocytes. Depletion of CD47 in the U87 cell line resulted in down-regulation of UHRF1. We also found that CD47 activated the inflammatory genes IL-6, IL-7 and MCP-1 by a NF-κB-dependent mechanism in human astrocytoma but not in normal astrocytes. In conclusion, the present findings indicate that CD47 activation increases expression of UHRF1 and suggest, for the first time, that CD47 regulates the epigenetic code by targeting UHRF1. This could represent a new pathway towards cell proliferation and metastasis.
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Boukhari
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Alhosin
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Parc d'innovation, Illkirch Cedex, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Krizia
authors.initials: K
authors.lastname: Sagini
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Truchot
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Sick
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: Schini-Kerth
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: André
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mély
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Mousli
authors.affiliation: CNRS UMR 7213 Laboratoire de Biophotonique et Pharmacologie, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France jean-pierre.gies@unistra.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gies
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051928:CD47 Antigen / Q000502:physiology*; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D051928:CD47 Antigen; C497894:CD47 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C508600:IL6 protein, human; C508605:IL7 protein, human; D015850:Interleukin-6; D015851:Interleukin-7; D016328:NF-kappa B; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Astrocytoma; CD47; NF-κB; UHRF1