title: Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma.
abstract: GLI1 oncogene has been implicated in the pathobiology of several neoplasms including diffuse large B-cell lymphoma (DLBCL). However, mechanisms underlying GLI1-increased activity in DLBCL are poorly characterized. Herein, we demonstrate that IKKβ phosphorylates GLI1 in DLBCL. IKKβ activation increased GLI1 protein levels and transcriptional activity, whereas IKKβ silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-α (TNFα) mediated IKKβ activation-impaired GLI1 binding with the E3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/degradation of GLI1. We found 8 IKKβ-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFα on GLI1 stability. IKKβ-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKβ-mediated nuclear factor-κB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL.
authors.affiliation: Division of Hematopathology, Department of Pathology.
authors.forename: Nitin K
authors.initials: NK
authors.lastname: Agarwal
authors.affiliation: Division of Hematopathology, Department of Pathology.
authors.forename: Chae H
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Division of Hematopathology, Department of Pathology.
authors.forename: Kranthi
authors.initials: K
authors.lastname: Kunkalla
authors.affiliation: Department of Cell Biology.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Konno
authors.affiliation: Division of Hematopathology, Department of Pathology.
authors.forename: Youley
authors.initials: Y
authors.lastname: Tjendra
authors.affiliation: Biostatistics and Bioinformatics Core.
authors.forename: Deukwoo
authors.initials: D
authors.lastname: Kwon
authors.affiliation: Division of Hematology-Oncology, Department of Medicine.
authors.forename: Marzenna
authors.initials: M
authors.lastname: Blonska
authors.affiliation: Division of Hematology-Oncology, Department of Medicine.
authors.forename: Goldi A
authors.initials: GA
authors.lastname: Kozloski
authors.affiliation: Department of Physiology and Biophysics, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Moy
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; and.
authors.forename: Ramiro E
authors.initials: RE
authors.lastname: Verdun
authors.affiliation: Department of Cell Biology.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Division of Hematology-Oncology, Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.affiliation: Division of Hematopathology, Department of Pathology, Division of Hematology-Oncology, Department of Medicine.
authors.forename: Francisco
authors.initials: F
authors.lastname: Vega
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D055550:Protein Stability; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D016328:NF-kappa B; D012097:Repressor Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D051550:I-kappa B Kinase