title: The inhibitor of growth 1 (ING1) is involved in trichostatin A-induced apoptosis and caspase 3 signaling in p53-deficient glioblastoma cells.
abstract: Prognosis for patients with glioblastoma multiforme (GBM) is poor. Inhibitors of histone deacetylases (HDACi) like trichostatin A (TSA) are promising alternatives to conventional treatment. Deficient tumor suppressor functions, such as TP53 mutations and p14(ARF)/p16(INK4a) deletions, are characteristic for GBM and can cause resistance to DNA damaging agents such as cisplatin and to HDACi like TSA. The type II tumor suppressor Inhibitor of growth 1 (ING1) is involved in DNA damage response and histone modification. We have previously shown that ING1 is downregulated in GBM and involved in glioma-induced angiogenesis and in cisplatin-induced apoptosis in malignant glioma cells. Hence, the goal of our present study was to investigate whether TSA affects ING1 protein expression and also whether modulating ING1 levels affects TSA-induced apoptosis in malignant glioma cells that contain deficient p53 function and inactive pl4(ARF)/p16(INK4a) signaling. If so, we asked, which apoptotic pathway might be the major mediator beyond this interaction. To test whether ING1 proteins function in TSA-induced apoptosis in GBM, we analyzed TSA effects in LN229 GBM cells, which harbor TP53 mutations and INK4a deletion, following ING1 knockdown by siRNA. Expression of ING1, acetylated core histones H3 and H4, and the proapoptotic proteins caspase 3 and Fas-associated death domain (FADD) was determined by Western blotting. Percentages of apoptotic cells were obtained by flow cytometry. TSA induced the major ING1 isoform p33(ING1b) and increased levels of both histone acetylation and apoptosis in LN229 cells. ING1 knockdown cells revealed marked resistance to TSA-induced apoptosis, impairment of caspase 3 activation, and suppression of FADD. The data suggest that ING1 contributes to TSA-induced apoptosis in GBM cells with deficient p53 and p14(ARF)/p16(INK4a) functions, possibly by regulating FADD/caspase 3 signaling.
authors.affiliation: Department of Pediatric Oncology/Haematology, Charité, Universitätsmedizin-Berlin, Berlin, Germany.
authors.forename: Mona
authors.initials: M
authors.lastname: Tamannai
authors.forename: Sonja
authors.initials: S
authors.lastname: Farhangi
authors.forename: Matthias
authors.initials: M
authors.lastname: Truss
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sinn
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wurm
authors.forename: Pinaki
authors.initials: P
authors.lastname: Bose
authors.forename: Guenter
authors.initials: G
authors.lastname: Henze
authors.forename: Karl
authors.initials: K
authors.lastname: Riabowol
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Gesche
authors.initials: G
authors.lastname: Tallen
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000502:physiology*; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000032:analysis; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D053148:Caspase 3