Active IKKb promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Nitin K. Agarwal; Chae H. Kim; Kranthi Kunkalla; Hiroyasu Konno; Youley Tjendra; Deukwoo Kwon; Marzenna Blonska; Goldi A. Kozloski; Vincent T. Moy; Ramiro E. Verdun; Glen N. Barber; Izidore S. Lossos; Francisco Vega

doi:10.1182/blood-2015-07-658781

Active IKKb promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Nitin K. Agarwal, Chae H. Kim, Kranthi Kunkalla, Hiroyasu Konno, Youley Tjendra, Deukwoo Kwon, Marzenna Blonska, Goldi A. Kozloski, Vincent T. Moy, Ramiro E. Verdun, Glen N. Barber, Izidore S. Lossos, Francisco Vega

Molecular & Cellular Oncology

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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 IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-A (TNFa) mediated IKKb activation-impaired GLI1 binding with theE3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL.

Original language	English (US)
Pages (from-to)	605-615
Number of pages	11
Journal	Blood
Volume	127
Issue number	5
DOIs	https://doi.org/10.1182/blood-2015-07-658781
State	Published - Feb 4 2016

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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title = "Active IKKb 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 IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-A (TNFa) mediated IKKb activation-impaired GLI1 binding with theE3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL.",

author = "Agarwal, {Nitin K.} and Kim, {Chae H.} and Kranthi Kunkalla and Hiroyasu Konno and Youley Tjendra and Deukwoo Kwon and Marzenna Blonska and Kozloski, {Goldi A.} and Moy, {Vincent T.} and Verdun, {Ramiro E.} and Barber, {Glen N.} and Lossos, {Izidore S.} and Francisco Vega",

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doi = "10.1182/blood-2015-07-658781",

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T1 - Active IKKb promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

AU - Agarwal, Nitin K.

AU - Kim, Chae H.

AU - Kunkalla, Kranthi

AU - Konno, Hiroyasu

AU - Tjendra, Youley

AU - Kwon, Deukwoo

AU - Blonska, Marzenna

AU - Kozloski, Goldi A.

AU - Moy, Vincent T.

AU - Verdun, Ramiro E.

AU - Barber, Glen N.

AU - Lossos, Izidore S.

AU - Vega, Francisco

PY - 2016/2/4

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N2 - 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 IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-A (TNFa) mediated IKKb activation-impaired GLI1 binding with theE3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL.

AB - 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 IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-A (TNFa) mediated IKKb activation-impaired GLI1 binding with theE3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL.

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Active IKKb promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Abstract

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